bims-proteo 2023-01-29 papers

bims-proteo

Biomed News

on Proteostasis

Issue of 2023‒01‒29
29 papers selected by
Eric Chevet
INSERM

Ectopic RING activity at the ER membrane differentially impacts ERAD protein quality control pathways.
MitoStores: chaperone-controlled protein granules store mitochondrial precursors in the cytosol.
Visualization of translation and protein biogenesis at the ER membrane.
Yeast derlin Dfm1 employs a chaperone-like function to resolve misfolded membrane protein stress.
Stress granule homeostasis is modulated by TRIM21-mediated ubiquitination of G3BP1 and autophagy-dependent elimination of stress granules.
The selective autophagy adaptor p62/SQSTM1 forms phase condensates regulated by HSP27 that facilitate the clearance of damaged lysosomes via lysophagy.
Ufmylation reconciles salt stress-induced unfolded protein responses via ER-phagy in Arabidopsis.
Tex2 is required for lysosomal functions at TMEM55-dependent ER membrane contact sites.
FUS ALS neurons activate major stress pathways and reduce translation as an early protective mechanism against neurodegeneration.
Loss of ATF6α in a Human Carcinoma Cell Line Is Compensated not by Its Paralogue ATF6β but by Sustained Activation of the IRE1 and PERK Arms for Tumor Growth in Nude Mice.
The GET pathway serves to activate Atg32-mediated mitophagy by ER targeting of the Ppg1-Far complex.
Multiple phosphorylation of the Cdc48/p97 cofactor protein Shp1/p47 occurs upon cell stress in budding yeast.
Advancing Targeted Protein Degradation via Multiomics Profiling and Artificial Intelligence.
Infancy-onset diabetes caused by de-regulated AMPylation of the human endoplasmic reticulum chaperone BiP.
Defective proteostasis in Alzheimer's disease.
TORC1 phosphorylates and inhibits the ribosome preservation factor Stm1 to activate dormant ribosomes.
Ubiquitin-Mediated Regulation of Autophagy During Viral Infection.
Mitochondrial remodelling is essential for female germ cell differentiation and survival.
Mitochondrial complexome reveals quality-control pathways of protein import.
Small heat shock proteins operate as molecular chaperones in the mitochondrial intermembrane space.
ADP-ribose transferase PARP16 mediated-unfolded protein response contributes to neuronal cell damage in cerebral ischemia/reperfusion.
Towards a structurally resolved human protein interaction network.
VAP-A intrinsically disordered regions enable versatile tethering at membrane contact sites.
SUMOylation-mediated PSME3-20S proteasomal degradation of transcription factor CP2c is crucial for cell cycle progression.
A glaucoma-associated OPTN polymorphism, M98K sensitizes retinal cells to endoplasmic reticulum stress and tumor necrosis factor α.
Oncogenic PKA signaling increases c-MYC protein expression through multiple targetable mechanisms.
Immunoproteasome inhibition prevents progression of castration-resistant prostate cancer.
Lamin A/C phosphorylation at serine 22 is a conserved heat shock response to regulate nuclear adaptation during stress.
NEDD8-conjugating enzyme E2s: critical targets for cancer therapy.

J Biol Chem. 2023 Jan 19. pii: S0021-9258(23)00059-5. [Epub ahead of print] 102927

Ectopic RING activity at the ER membrane differentially impacts ERAD protein quality control pathways.

Adrian B Mehrtash, Mark Hochstrasser.

  Endoplasmic reticulum-associated degradation (ERAD) is a protein quality control pathway that ensures misfolded proteins are removed from the ER and destroyed. In ERAD, membrane and luminal substrates are ubiquitylated by ER-resident RING-type E3 ubiquitin ligases, retrotranslocated into the cytosol, and degraded by the proteasome. Overexpression of ERAD factors is frequently used in yeast and mammalian cells to study this process. Here we analyze the impact of ERAD E3 overexpression on substrate turnover in yeast, where there are three ERAD E3 complexes (Doa10, Hrd1, and Asi1-3). Elevated Doa10 or Hrd1 (but not Asi1) RING activity at the ER membrane resulting from protein overexpression inhibits the degradation of specific Doa10 substrates. The ERAD E2 ubiquitin-conjugating enzyme Ubc6 becomes limiting under these conditions, and UBC6 overexpression restores Ubc6-mediated ERAD. Using a subset of the dominant-negative mutants, which contain the Doa10 RING domain but lack the E2-binding region, we show that they induce degradation of membrane tail-anchored Ubc6 independently of endogenous Doa10 and the other ERAD E3 complexes. This remains true even if the cells lack the Dfm1 rhomboid pseudoprotease, which is also a proposed retrotranslocon. Hence, rogue RING activity at the ER membrane elicits a highly specific off-pathway defect in the Doa10 pathway, and the data point to an additional ERAD E3-independent retrotranslocation mechanism.

Keywords:  Doa10; Protein degradation; endoplasmic reticulum; endoplasmic-reticulum-associated degradation (ERAD); protein quality control; retrotranslocation; ubiquitin; ubiquitin ligase; ubiquitin-conjugating enzyme; yeast

DOI:  https://doi.org/10.1016/j.jbc.2023.102927
EMBO J. 2023 Jan 27. e112309

MitoStores: chaperone-controlled protein granules store mitochondrial precursors in the cytosol.

Lena Krämer, Niko Dalheimer, Markus Räschle, Zuzana Storchová, Jan Pielage, Felix Boos, Johannes M Herrmann.

  Hundreds of nucleus-encoded mitochondrial precursor proteins are synthesized in the cytosol and imported into mitochondria in a post-translational manner. However, the early processes associated with mitochondrial protein targeting remain poorly understood. Here, we show that in Saccharomyces cerevisiae, the cytosol has the capacity to transiently store mitochondrial matrix-destined precursors in dedicated deposits that we termed MitoStores. Competitive inhibition of mitochondrial protein import via clogging of import sites greatly enhances the formation of MitoStores, but they also form during physiological cell growth on nonfermentable carbon sources. MitoStores are enriched for a specific subset of nucleus-encoded mitochondrial proteins, in particular those containing N-terminal mitochondrial targeting sequences. Our results suggest that MitoStore formation suppresses the toxic potential of aberrantly accumulating mitochondrial precursor proteins and is controlled by the heat shock proteins Hsp42 and Hsp104. Thus, the cytosolic protein quality control system plays an active role during the early stages of mitochondrial protein targeting through the coordinated and localized sequestration of mitochondrial precursor proteins.

Keywords:  chaperones; mitochondria; proteasome; protein aggregates; protein translocation

DOI:  https://doi.org/10.15252/embj.2022112309
Nature. 2023 Jan 25.

Visualization of translation and protein biogenesis at the ER membrane.

Max Gemmer, Marten L Chaillet, Joyce van Loenhout, Rodrigo Cuevas Arenas, Dimitrios Vismpas, Mariska Gröllers-Mulderij, Fujiet A Koh, Pascal Albanese, Richard A Scheltema, Stuart C Howes, Abhay Kotecha, Juliette Fedry, Friedrich Förster.

The dynamic ribosome-translocon complex, which resides at the endoplasmic reticulum (ER) membrane, produces a major fraction of the human proteome1,2. It governs the synthesis, translocation, membrane insertion, N-glycosylation, folding and disulfide-bond formation of nascent proteins. Although individual components of this machinery have been studied at high resolution in isolation3-7, insights into their interplay in the native membrane remain limited. Here we use cryo-electron tomography, extensive classification and molecular modelling to capture snapshots of mRNA translation and protein maturation at the ER membrane at molecular resolution. We identify a highly abundant classical pre-translocation intermediate with eukaryotic elongation factor 1a (eEF1a) in an extended conformation, suggesting that eEF1a may remain associated with the ribosome after GTP hydrolysis during proofreading. At the ER membrane, distinct polysomes bind to different ER translocons specialized in the synthesis of proteins with signal peptides or multipass transmembrane proteins with the translocon-associated protein complex (TRAP) present in both. The near-complete atomic model of the most abundant ER translocon variant comprising the protein-conducting channel SEC61, TRAP and the oligosaccharyltransferase complex A (OSTA) reveals specific interactions of TRAP with other translocon components. We observe stoichiometric and sub-stoichiometric cofactors associated with OSTA, which are likely to include protein isomerases. In sum, we visualize ER-bound polysomes with their coordinated downstream machinery.

DOI: https://doi.org/10.1038/s41586-022-05638-5
PLoS Biol. 2023 Jan 23. 21(1): e3001950

Yeast derlin Dfm1 employs a chaperone-like function to resolve misfolded membrane protein stress.

Rachel Kandel, Jasmine Jung, Della Syau, Tiffany Kuo, Livia Songster, Casey Horn, Claire Chapman, Analine Aguayo, Sascha Duttke, Christopher Benner, Sonya E Neal.

Protein aggregates are a common feature of diseased and aged cells. Membrane proteins comprise a quarter of the proteome, and yet, it is not well understood how aggregation of membrane proteins is regulated and what effects these aggregates can have on cellular health. We have determined in yeast that the derlin Dfm1 has a chaperone-like activity that influences misfolded membrane protein aggregation. We establish that this function of Dfm1 does not require recruitment of the ATPase Cdc48 and it is distinct from Dfm1's previously identified function in dislocating misfolded membrane proteins from the endoplasmic reticulum (ER) to the cytosol for degradation. Additionally, we assess the cellular impacts of misfolded membrane proteins in the absence of Dfm1 and determine that misfolded membrane proteins are toxic to cells in the absence of Dfm1 and cause disruptions to proteasomal and ubiquitin homeostasis.

DOI: https://doi.org/10.1371/journal.pbio.3001950
Autophagy. 2023 Jan 24. 1-18

Stress granule homeostasis is modulated by TRIM21-mediated ubiquitination of G3BP1 and autophagy-dependent elimination of stress granules.

Cuiwei Yang, Zhangshun Wang, Yingjin Kang, Qianqian Yi, Tong Wang, Yun Bai, Yanfen Liu.

  Eukaryotic stress granules (SGs) are highly dynamic assemblies of untranslated mRNAs and proteins that form through liquid-liquid phase separation (LLPS) under cellular stress. SG formation and elimination process is a conserved cellular strategy to promote cell survival, although the precise regulation of this process is poorly understood. Here, we screened six E3 ubiquitin ligases present in SGs and identified TRIM21 (tripartite motif containing 21) as a central regulator of SG homeostasis that is highly enriched in SGs of cells under arsenite-induced oxidative stress. Knockdown of TRIM21 promotes SG formation whereas overexpression of TRIM21 inhibits the formation of physiological and pathological SGs associated with neurodegenerative diseases. TRIM21 catalyzes K63-linked ubiquitination of the SG core protein, G3BP1 (G3BP stress granule assembly factor 1), and G3BP1 ubiquitination can effectively inhibit LLPS, in vitro. Recent reports suggested the involvement of macroautophagy/autophagy, as a stress response pathway, in the regulation of SG homeostasis. We systematically investigated well-defined autophagy receptors and identified SQSTM1/p62 (sequestosome 1) and CALCOCO2/NDP52 (calcium binding and coiled-coil domain 2) as the primary receptors that directly interact with G3BP1 during arsenite-induced stress. Endogenous SQSTM1 and CALCOCO2 localize to the periphery of SGs under oxidative stress and mediate SG elimination, as single knockout of each receptor causes accumulation of physiological and pathological SGs. Collectively, our study broadens the understanding in the regulation of SG homeostasis by showing that TRIM21 and autophagy receptors modulate SG formation and elimination respectively, suggesting the possibility of clinical targeting of these molecules in therapeutic strategies for neurodegenerative diseases.Abbreviations: ACTB: actin beta; ALS: amyotrophic lateral sclerosis; BafA1: bafilomycin A1; BECN1: beclin 1; C9orf72: C9orf72-SMCR8 complex subunit; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; Co-IP: co-immunoprecipitation; DAPI: 4',6-diamidino-2-phenylindole; FTD: frontotemporal dementia; FUS: FUS RNA binding protein; G3BP1: G3BP stress granule assembly factor 1; GFP: green fluorescent protein; LLPS: liquid-liquid phase separation; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; NBR1: NBR1 autophagy cargo receptor; NES: nuclear export signal; OPTN: optineurin; RFP: red fluorescent protein; SQSTM1/p62: sequestosome 1; SG: stress granule; TAX1BP1: Tax1 binding protein 1; TOLLIP: toll interacting protein; TRIM21: tripartite motif containing 21; TRIM56: tripartite motif containing 56; UB: ubiquitin; ULK1: unc-51 like autophagy activating kinase 1; WT: wild-type.

Keywords:  Autophagy receptor; CALCOCO2; G3BP1; SQSTM1; TRIM21; stress granule; ubiquitination

DOI:  https://doi.org/10.1080/15548627.2022.2164427
Cell Rep. 2023 Jan 25. pii: S2211-1247(23)00048-7. [Epub ahead of print]42(2): 112037

The selective autophagy adaptor p62/SQSTM1 forms phase condensates regulated by HSP27 that facilitate the clearance of damaged lysosomes via lysophagy.

Elizabeth R Gallagher, Erika L F Holzbaur.

  In response to lysosomal damage, cells engage several quality-control mechanisms, including the selective isolation and degradation of damaged lysosomes by lysophagy. Here, we report that the selective autophagy adaptor SQSTM1/p62 is recruited to damaged lysosomes in both HeLa cells and neurons and is required for lysophagic flux. The Phox and Bem1p (PB1) domain of p62 mediates oligomerization and is specifically required for lysophagy. Consistent with this observation, we find that p62 forms condensates on damaged lysosomes. These condensates are precisely tuned by the small heat shock protein HSP27, which is phosphorylated in response to lysosomal injury and maintains the liquidity of p62 condensates, facilitating autophagosome formation. Mutations in p62 have been identified in patients with amyotrophic lateral sclerosis (ALS); ALS-associated mutations in p62 impair lysophagy, suggesting that deficits in this pathway may contribute to neurodegeneration. Thus, p62 condensates regulated by HSP27 promote lysophagy by forming platforms for autophagosome biogenesis at damaged lysosomes.

Keywords:  ALS; CP: Cell biology; CP: Neuroscience; HSP27; autophagy; condensates; lysophagy; lysosome; neurodegeneration; neurons; p62/SQSTM1; phase separation

DOI:  https://doi.org/10.1016/j.celrep.2023.112037
Proc Natl Acad Sci U S A. 2023 Jan 31. 120(5): e2208351120

Ufmylation reconciles salt stress-induced unfolded protein responses via ER-phagy in Arabidopsis.

Baiying Li, Fangfang Niu, Yonglun Zeng, Man Kei Tse, Cesi Deng, Liu Hong, Shengyu Gao, Sze Wan Lo, Wenhan Cao, Shuxian Huang, Yasin Dagdas, Liwen Jiang.

In plants, the endomembrane system is tightly regulated in response to environmental stresses for maintaining cellular homeostasis. Autophagosomes, the double membrane organelles forming upon nutrient deprivation or stress induction, degrade bulky cytosolic materials for nutrient turnover. Though abiotic stresses have been reported to induce plant autophagy, few receptors or regulators for selective autophagy have been characterized for specific stresses. Here, we have applied immunoprecipitation followed by tandem mass spectrometry using the autophagosome marker protein ATG8 as bait and have identified the E3 ligase of the ufmylation system Ufl1 as a bona fide ATG8 interactor under salt stress. Notably, core components in the ufmylation cascade, Ufl1 and Ufm1, interact with the autophagy kinase complexes proteins ATG1 and ATG6. Cellular and genetic analysis showed that Ufl1 is important for endoplasmic reticulum (ER)-phagy under persisting salt stress. Loss-of-function mutants of Ufl1 display a salt stress hypersensitive phenotype and abnormal ER morphology. Prolonged ER stress responses are detected in ufl1 mutants that phenocopy the autophagy dysfunction atg5 mutants. Consistently, expression of ufmylation cascade components is up-regulated by salt stress. Taken together, our study demonstrates the role of ufmylation in regulating ER homeostasis under salt stress through ER-phagy.

DOI: https://doi.org/10.1073/pnas.2208351120
J Cell Biol. 2023 Apr 03. pii: e202205133. [Epub ahead of print]222(4):

Tex2 is required for lysosomal functions at TMEM55-dependent ER membrane contact sites.

Yuanjiao Du, Weiping Chang, Lei Gao, Lin Deng, Wei-Ke Ji.

ER tubules form and maintain membrane contact sites (MCSs) with late endosomes/lysosomes (LE/lys). The molecular composition and cellular functions of these MCSs are poorly understood. Here, we find that Tex2, an SMP domain-containing lipid transfer protein conserved in metazoan and yeast, is a tubular ER protein and is recruited to ER-LE/lys MCSs by TMEM55, phosphatases that convert PI(4,5)P2 to PI5P on LE/lys. We show that the Tex2-TMEM55 interaction occurs between an N-terminal region of Tex2 and a catalytic motif in the PTase domain of TMEM55. The Tex2-TMEM55 interaction can be regulated by endosome-resident type 2 PI4K activities. Functionally, Tex2 knockout results in defects in lysosomal trafficking, digestive capacity, and lipid composition of LE/lys membranes. Together, our data identify Tex2 as a tubular ER protein that resides at TMEM55-dependent ER-LE/lys MCSs required for lysosomal functions.

DOI: https://doi.org/10.1083/jcb.202205133
Cell Rep. 2023 Jan 24. pii: S2211-1247(23)00036-0. [Epub ahead of print]42(2): 112025

FUS ALS neurons activate major stress pathways and reduce translation as an early protective mechanism against neurodegeneration.

Barbara Szewczyk, René Günther, Julia Japtok, Moritz J Frech, Marcel Naumann, Hyun O Lee, Andreas Hermann.

  Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder causing progressive loss of motor neurons. Mutations in Fused in sarcoma (FUS) leading to its cytoplasmic mislocalization cause a subset of ALS. Under stress, mutant FUS localizes to stress granules (SGs)-cytoplasmic condensates composed of RNA and various proteins. Aberrant dynamics of SGs is linked to the pathology of ALS. Here, using motor neurons (MNs) derived from human induced pluripotent stem cells, we show that, in mutant FUS, MN dynamics of SGs is disturbed. Additionally, heat-shock response (HSR) and integrated stress response (ISR) involved in the regulation of SGs are upregulated in mutant MNs. HSR activation correlates with the amount of cytoplasmic FUS mislocalization. While inhibition of SG formation, translation, or ISR does not influence survival of FUS ALS neurons, proteotoxicity that cannot be compensated with the activation of stress pathways is the main driver of neurodegeneration in early FUS ALS.

Keywords:  CP: Neuroscience; FUS; amyotrophic lateral sclerosis; heat stress response; integrated stress response; neurodegeneration; protein translation; proteostasis; stress granules

DOI:  https://doi.org/10.1016/j.celrep.2023.112025
Mol Biol Cell. 2023 Jan 25. mbcE22070292

Loss of ATF6α in a Human Carcinoma Cell Line Is Compensated not by Its Paralogue ATF6β but by Sustained Activation of the IRE1 and PERK Arms for Tumor Growth in Nude Mice.

Shengyu Jin, Byungseok Jin, Tokiro Ishikawa, Satoshi Ninagawa, Tetsuya Okada, Sho Koyasu, Hiroshi Harada, Kazutoshi Mori.

To survive poor nutritional conditions, tumor cells activate the unfolded protein response, which is composed of the IRE1, PERK and ATF6 arms, to maintain the homeostasis of the endoplasmic reticulum, where secretory and transmembrane proteins destined for the secretory pathway gain their correct three dimensional structure. The requirement of the IRE1 and PERK arms for tumor growth in nude mice is established. Here, we investigated the requirement for the ATF6 arm, which consists of ubiquitously expressed ATF6α and ATF6β, by constructing ATF6α-knockout, ATF6β-knockout and ATF6α/β-double knockout in HCT116 cells derived from human colorectal carcinoma. Results showed that these knockout cells grew similarly to wild-type cells in nude mice, contrary to expectations from our analysis of ATF6α-knockout, ATF6β-knockout and ATF6α/β-double knockout mice. We then found that the loss of ATF6α in HCT116 cells resulted in sustained activation of the IRE1 and PERK arms, in marked contrast to mouse embryonic fibroblasts, in which the loss of ATF6α is compensated for by ATF6β. Although IRE1-knockout in HCT116 cells unexpectedly did not affect tumor growth in nude mice, IRE1-knockout HCT116 cells with ATF6α knockdown grew significantly more slowly than wild-type or IRE1-knockout HCT116 cells. These results have unraveled the situation-dependent differential compensation strategies of ATF6α.

DOI: https://doi.org/10.1091/mbc.E22-07-0292
Life Sci Alliance. 2023 Apr;pii: e202201640. [Epub ahead of print]6(4):

The GET pathway serves to activate Atg32-mediated mitophagy by ER targeting of the Ppg1-Far complex.

Mashun Onishi, Mitsutaka Kubota, Lan Duan, Yuan Tian, Koji Okamoto.

Mitophagy removes defective or superfluous mitochondria via selective autophagy. In yeast, the pro-mitophagic protein Atg32 localizes to the mitochondrial surface and interacts with the scaffold protein Atg11 to promote degradation of mitochondria. Although Atg32-Atg11 interactions are thought to be stabilized by Atg32 phosphorylation, how this posttranslational modification is regulated remains obscure. Here, we show that cells lacking the guided entry of the tail-anchored protein (GET) pathway exhibit reduced Atg32 phosphorylation and Atg32-Atg11 interactions, which can be rescued by additional loss of the ER-resident Ppg1-Far complex, a multi-subunit phosphatase negatively acting in mitophagy. In GET-deficient cells, Ppg1-Far is predominantly localized to mitochondria. An artificial ER anchoring of Ppg1-Far in GET-deficient cells significantly ameliorates defects in Atg32-Atg11 interactions and mitophagy. Moreover, disruption of GET and Msp1, an AAA-ATPase that extracts non-mitochondrial proteins localized to the mitochondrial surface, elicits synthetic defects in mitophagy. Collectively, we propose that the GET pathway mediates ER targeting of Ppg1-Far, thereby preventing dysregulated suppression of mitophagy activation.

DOI: https://doi.org/10.26508/lsa.202201640
Life Sci Alliance. 2023 Apr;pii: e202201642. [Epub ahead of print]6(4):

Multiple phosphorylation of the Cdc48/p97 cofactor protein Shp1/p47 occurs upon cell stress in budding yeast.

Alexander Agrotis, Frederic Lamoliatte, Thomas D Williams, Ailsa Black, Rhuari Horberry, Adrien Rousseau.

The homohexameric p97 complex, composed of Cdc48 subunits in yeast, is a crucial component of protein quality control pathways including ER-associated degradation. The complex acts to segregate protein complexes in an ATP-dependent manner, requiring the engagement of cofactor proteins that determine substrate specificity. The function of different Cdc48 cofactors and how they are regulated remains relatively poorly understood. In this study, we assess the phosphorylation of Cdc48 adaptor proteins, revealing a unique and distinctive phosphorylation pattern of Shp1/p47 that changed in response to TORC1 inhibition. Site-directed mutagenesis confirmed that this pattern corresponded to phosphorylation at residues S108 and S315 of Shp1, with the double-phosphorylated form becoming predominant upon TORC1 inhibition, ER-stress, and oxidative stress. Finally, we assessed candidate kinases and phosphatases responsible for Shp1 phosphorylation and identified two regulators. We found that cells lacking the kinase Mpk1/Slt2 show reduced Shp1 phosphorylation, whereas impaired PP1 phosphatase catalytic subunit (Glc7) activity resulted in increased Shp1 phosphorylation. Overall, these findings identify a phosphoregulation of Shp1 at multiple sites by Mpk1 kinase and PP1 phosphatase upon various stresses.

DOI: https://doi.org/10.26508/lsa.202201642
J Am Chem Soc. 2023 Jan 27.

Advancing Targeted Protein Degradation via Multiomics Profiling and Artificial Intelligence.

Miquel Duran-Frigola, Marko Cigler, Georg E Winter.

Only around 20% of the human proteome is considered to be druggable with small-molecule antagonists. This leaves some of the most compelling therapeutic targets outside the reach of ligand discovery. The concept of targeted protein degradation (TPD) promises to overcome some of these limitations. In brief, TPD is dependent on small molecules that induce the proximity between a protein of interest (POI) and an E3 ubiquitin ligase, causing ubiquitination and degradation of the POI. In this perspective, we want to reflect on current challenges in the field, and discuss how advances in multiomics profiling, artificial intelligence, and machine learning (AI/ML) will be vital in overcoming them. The presented roadmap is discussed in the context of small-molecule degraders but is equally applicable for other emerging proximity-inducing modalities.

DOI: https://doi.org/10.1021/jacs.2c11098
EMBO Mol Med. 2023 Jan 27. e16491

Infancy-onset diabetes caused by de-regulated AMPylation of the human endoplasmic reticulum chaperone BiP.

Luke A Perera, Andrew T Hattersley, Heather P Harding, Matthew N Wakeling, Sarah E Flanagan, Ibrahim Mohsina, Jamal Raza, Alice Gardham, David Ron, Elisa De Franco.

  Dysfunction of the endoplasmic reticulum (ER) in insulin-producing beta cells results in cell loss and diabetes mellitus. Here we report on five individuals from three different consanguineous families with infancy-onset diabetes mellitus and severe neurodevelopmental delay caused by a homozygous p.(Arg371Ser) mutation in FICD. The FICD gene encodes a bifunctional Fic domain-containing enzyme that regulates the ER Hsp70 chaperone, BiP, via catalysis of two antagonistic reactions: inhibitory AMPylation and stimulatory deAMPylation of BiP. Arg371 is a conserved residue in the Fic domain active site. The FICDR371S mutation partially compromises BiP AMPylation in vitro but eliminates all detectable deAMPylation activity. Overexpression of FICDR371S or knock-in of the mutation at the FICD locus of stressed CHO cells results in inappropriately elevated levels of AMPylated BiP and compromised secretion. These findings, guided by human genetics, highlight the destructive consequences of de-regulated BiP AMPylation and raise the prospect of tuning FICD's antagonistic activities towards therapeutic ends.

Keywords:  diabetes mellitus; endoplasmic reticulum chaperone; mutation; nucleotidyltransferases; post-translational

DOI:  https://doi.org/10.15252/emmm.202216491
Ageing Res Rev. 2023 Jan 21. pii: S1568-1637(23)00021-1. [Epub ahead of print]85 101862

Defective proteostasis in Alzheimer's disease.

Danielle Cozachenco, Felipe C Ribeiro, Sergio T Ferreira.

  The homeostasis of cellular proteins, or proteostasis, is critical for neuronal function and for brain processes, including learning and memory. Increasing evidence indicates that defective proteostasis contributes to the progression of neurodegenerative disorders, including Alzheimer's disease (AD), the most prevalent form of dementia in the elderly. Proteostasis comprises a set of cellular mechanisms that control protein synthesis, folding, post-translational modification and degradation, all of which are deregulated in AD. Importantly, deregulation of proteostasis plays a key role in synapse dysfunction and in memory impairment, the major clinical manifestation of AD. Here, we discuss molecular pathways involved in protein synthesis and degradation that are altered in AD, and possible pharmacological approaches to correct these defects.

Keywords:  Alzheimer’s disease; Amyloid-β oligomers; Autophagy; Degradation; ER stress; Protein synthesis; Proteostasis; Ubiquitin-proteasome system

DOI:  https://doi.org/10.1016/j.arr.2023.101862
EMBO J. 2023 Jan 24. e112344

TORC1 phosphorylates and inhibits the ribosome preservation factor Stm1 to activate dormant ribosomes.

Sunil Shetty, Jon Hofstetter, Stefania Battaglioni, Danilo Ritz, Michael N Hall.

  Target of rapamycin complex 1 (TORC1) promotes biogenesis and inhibits the degradation of ribosomes in response to nutrient availability. To ensure a basal supply of ribosomes, cells are known to preserve a small pool of dormant ribosomes under nutrient-limited conditions. However, the regulation of these dormant ribosomes is poorly characterized. Here, we show that upon inhibition of yeast TORC1 by rapamycin or nitrogen starvation, the ribosome preservation factor Stm1 mediates the formation of nontranslating, dormant 80S ribosomes. Furthermore, Stm1-bound 80S ribosomes are protected from proteasomal degradation. Upon nutrient replenishment, TORC1 directly phosphorylates and inhibits Stm1 to reactivate translation. Finally, we find that SERBP1, a mammalian ortholog of Stm1, is likewise required for the formation of dormant 80S ribosomes upon mTORC1 inhibition in mammalian cells. These data suggest that TORC1 regulates ribosomal dormancy in an evolutionarily conserved manner by directly targeting a ribosome preservation factor.

Keywords:  SERBP1; Stm1; TORC1; dormant ribosomes; proteasome

DOI:  https://doi.org/10.15252/embj.2022112344
Curr Clin Microbiol Rep. 2023 Jan 13. 1-8

Ubiquitin-Mediated Regulation of Autophagy During Viral Infection.

Joydeep Nag, Janvi Patel, Shashank Tripathi.

  Purpose of Review: Virus infections skew the host autophagic response to meet their replication and transmission demands by tapping into the critical host regulatory mechanisms that control the autophagic flux. This review is a compendium of previous reports highlighting the mechanisms that viruses adapt to hijack the host ubiquitination machinery to repurpose autophagy for their sustenance.Recent Findings: Emerging evidence suggests a critical role of host ubiquitin machinery in the manifestation of the antiviral or proviral functions of autophagy. Lately, more emphasis has been laid to identify specific host E3 ubiquitin ligases, their targets (viral or host), and characterizing corresponding ubiquitin linkages by biochemical or genome-wide genetic screening approaches.
Summary: Here, we highlight how viruses ingeniously engage and subvert the host ubiquitin-autophagy system to promote virus replication and antagonize intracellular innate immune responses.

Keywords:  Autophagy; Innate immunity; Interferon; Proteasome; Ubiquitin; Virus

DOI:  https://doi.org/10.1007/s40588-022-00186-y
PLoS Genet. 2023 Jan 25. 19(1): e1010610

Mitochondrial remodelling is essential for female germ cell differentiation and survival.

Vernon Leander Monteiro, Darya Safavian, Deepika Vasudevan, Thomas Ryan Hurd.

Stem cells often possess immature mitochondria with few inner membrane invaginations, which increase as stem cells differentiate. Despite this being a conserved feature across many stem cell types in numerous organisms, how and why mitochondria undergo such remodelling during stem cell differentiation has remained unclear. Here, using Drosophila germline stem cells (GSCs), we show that Complex V drives mitochondrial remodelling during the early stages of GSC differentiation, prior to terminal differentiation. This endows germline mitochondria with the capacity to generate large amounts of ATP required for later egg growth and development. Interestingly, impairing mitochondrial remodelling prior to terminal differentiation results in endoplasmic reticulum (ER) lipid bilayer stress, Protein kinase R-like ER kinase (PERK)-mediated activation of the Integrated Stress Response (ISR) and germ cell death. Taken together, our data suggest that mitochondrial remodelling is an essential and tightly integrated aspect of stem cell differentiation. This work sheds light on the potential impact of mitochondrial dysfunction on stem and germ cell function, highlighting ER lipid bilayer stress as a potential major driver of phenotypes caused by mitochondrial dysfunction.

DOI: https://doi.org/10.1371/journal.pgen.1010610
Nature. 2023 Jan 25.

Mitochondrial complexome reveals quality-control pathways of protein import.

Uwe Schulte, Fabian den Brave, Alexander Haupt, Arushi Gupta, Jiyao Song, Catrin S Müller, Jeannine Engelke, Swadha Mishra, Christoph Mårtensson, Lars Ellenrieder, Chantal Priesnitz, Sebastian P Straub, Kim Nguyen Doan, Bogusz Kulawiak, Wolfgang Bildl, Heike Rampelt, Nils Wiedemann, Nikolaus Pfanner, Bernd Fakler, Thomas Becker.

Mitochondria have crucial roles in cellular energetics, metabolism, signalling and quality control1-4. They contain around 1,000 different proteins that often assemble into complexes and supercomplexes such as respiratory complexes and preprotein translocases1,3-7. The composition of the mitochondrial proteome has been characterized1,3,5,6; however, the organization of mitochondrial proteins into stable and dynamic assemblies is poorly understood for major parts of the proteome1,4,7. Here we report quantitative mapping of mitochondrial protein assemblies using high-resolution complexome profiling of more than 90% of the yeast mitochondrial proteome, termed MitCOM. An analysis of the MitCOM dataset resolves >5,200 protein peaks with an average of six peaks per protein and demonstrates a notable complexity of mitochondrial protein assemblies with distinct appearance for respiration, metabolism, biogenesis, dynamics, regulation and redox processes. We detect interactors of the mitochondrial receptor for cytosolic ribosomes, of prohibitin scaffolds and of respiratory complexes. The identification of quality-control factors operating at the mitochondrial protein entry gate reveals pathways for preprotein ubiquitylation, deubiquitylation and degradation. Interactions between the peptidyl-tRNA hydrolase Pth2 and the entry gate led to the elucidation of a constitutive pathway for the removal of preproteins. The MitCOM dataset-which is accessible through an interactive profile viewer-is a comprehensive resource for the identification, organization and interaction of mitochondrial machineries and pathways.

DOI: https://doi.org/10.1038/s41586-022-05641-w
Nat Cell Biol. 2023 Jan 23.

Small heat shock proteins operate as molecular chaperones in the mitochondrial intermembrane space.

Elias Adriaenssens, Bob Asselbergh, Pablo Rivera-Mejías, Sven Bervoets, Leen Vendredy, Vicky De Winter, Katrien Spaas, Riet de Rycke, Gert van Isterdael, Francis Impens, Thomas Langer, Vincent Timmerman.

Mitochondria are complex organelles with different compartments, each harbouring their own protein quality control factors. While chaperones of the mitochondrial matrix are well characterized, it is poorly understood which chaperones protect the mitochondrial intermembrane space. Here we show that cytosolic small heat shock proteins are imported under basal conditions into the mitochondrial intermembrane space, where they operate as molecular chaperones. Protein misfolding in the mitochondrial intermembrane space leads to increased recruitment of small heat shock proteins. Depletion of small heat shock proteins leads to mitochondrial swelling and reduced respiration, while aggregation of aggregation-prone substrates is countered in their presence. Charcot-Marie-Tooth disease-causing mutations disturb the mitochondrial function of HSPB1, potentially linking previously observed mitochondrial dysfunction in Charcot-Marie-Tooth type 2F to its role in the mitochondrial intermembrane space. Our results reveal that small heat shock proteins form a chaperone system that operates in the mitochondrial intermembrane space.

DOI: https://doi.org/10.1038/s41556-022-01074-9
FASEB J. 2023 Feb;37(2): e22788

ADP-ribose transferase PARP16 mediated-unfolded protein response contributes to neuronal cell damage in cerebral ischemia/reperfusion.

Jinghuan Wang, Jie Xu, Yejun Dong, Zhenghua Su, Haibi Su, Qianwen Cheng, Xinhua Liu.

  Ischemic stroke is known to cause the accumulation of misfolded proteins and loss of calcium homeostasis, leading to impairment of endoplasmic reticulum (ER) function and activating the unfolded protein response (UPR). PARP16 is an active (ADP-ribosyl)transferase known tail-anchored ER transmembrane protein with a cytosolic catalytic domain. Here, we find PARP16 is highly expressed in ischemic cerebral hemisphere and oxygen-glucose deprivation/reoxygenation (OGD/R)-treated immortalized hippocampal neuronal cell HT22. Using an adeno-associated virus-mediated PARP16 knockdown approach in mice, we find PARP16 knockdown decreases infarct demarcations and has a better neurological outcome after ischemic stroke. Our data indicate PARP16 knockdown decreases ER stress and neuronal death caused by OGD/R, whereas PARP16 overexpression promotes ER stress-mediated cell damage in primary cortical neurons. Furthermore, PARP16 functions mechanistically as ADP-ribosyltransferase to modulate the level of ADP-ribosylation of the corresponding PERK and IRE1α arm of the UPR, and such modifications mediate activation of PERK and IRE1α. Indeed, pharmacological stimulation of the UPR using Brefeldin A partly counteracts PARP16 knockdown-mediated neuronal protection upon OGD/R treatment. In conclusion, PARP16 plays a crucial role in post-ischemic UPR and PARP16 knockdown alleviates brain injury after ischemic stroke. This study demonstrates the potential of the PARP16-PERK/IRE1α axis as a target for neuronal survival in ischemic stroke.

Keywords:  PARP16; endoplasmic reticulum; ischemia stroke; neuronal cell; oxygen-glucose deprivation/reoxygenation

DOI:  https://doi.org/10.1096/fj.202201426RR
Nat Struct Mol Biol. 2023 Jan 23.

Towards a structurally resolved human protein interaction network.

David F Burke, Patrick Bryant, Inigo Barrio-Hernandez, Danish Memon, Gabriele Pozzati, Aditi Shenoy, Wensi Zhu, Alistair S Dunham, Pascal Albanese, Andrew Keller, Richard A Scheltema, James E Bruce, Alexander Leitner, Petras Kundrotas, Pedro Beltrao, Arne Elofsson.

Cellular functions are governed by molecular machines that assemble through protein-protein interactions. Their atomic details are critical to studying their molecular mechanisms. However, fewer than 5% of hundreds of thousands of human protein interactions have been structurally characterized. Here we test the potential and limitations of recent progress in deep-learning methods using AlphaFold2 to predict structures for 65,484 human protein interactions. We show that experiments can orthogonally confirm higher-confidence models. We identify 3,137 high-confidence models, of which 1,371 have no homology to a known structure. We identify interface residues harboring disease mutations, suggesting potential mechanisms for pathogenic variants. Groups of interface phosphorylation sites show patterns of co-regulation across conditions, suggestive of coordinated tuning of multiple protein interactions as signaling responses. Finally, we provide examples of how the predicted binary complexes can be used to build larger assemblies helping to expand our understanding of human cell biology.

DOI: https://doi.org/10.1038/s41594-022-00910-8
Dev Cell. 2023 Jan 23. pii: S1534-5807(22)00876-0. [Epub ahead of print]58(2): 121-138.e9

VAP-A intrinsically disordered regions enable versatile tethering at membrane contact sites.

Mélody Subra, Manuela Dezi, Joëlle Bigay, Sandra Lacas-Gervais, Aurélie Di Cicco, Ana Rita Dias Araújo, Sophie Abélanet, Lucile Fleuriot, Delphine Debayle, Romain Gautier, Amanda Patel, Fanny Roussi, Bruno Antonny, Daniel Lévy, Bruno Mesmin.

  Membrane contact sites (MCSs) are heterogeneous in shape, composition, and dynamics. Despite this diversity, VAP proteins act as receptors for multiple FFAT motif-containing proteins and drive the formation of most MCSs that involve the endoplasmic reticulum (ER). Although the VAP-FFAT interaction is well characterized, no model explains how VAP adapts to its partners in various MCSs. We report that VAP-A localization to different MCSs depends on its intrinsically disordered regions (IDRs) in human cells. VAP-A interaction with PTPIP51 and VPS13A at ER-mitochondria MCS conditions mitochondria fusion by promoting lipid transfer and cardiolipin buildup. VAP-A also enables lipid exchange at ER-Golgi MCS by interacting with oxysterol-binding protein (OSBP) and CERT. However, removing IDRs from VAP-A restricts its distribution and function to ER-mitochondria MCS. Our data suggest that IDRs do not modulate VAP-A preference toward specific partners but do adjust their geometry to MCS organization and lifetime constraints. Thus, IDR-mediated VAP-A conformational flexibility ensures membrane tethering plasticity and efficiency.

Keywords:  Golgi apparatus; VAP; cryo-EM; endoplasmic reticulum; intrinsically disordered region; lipid transfer protein; membrane contact site; membrane tethering; mitochondrial fusion; protein flexibility

DOI:  https://doi.org/10.1016/j.devcel.2022.12.010
Sci Adv. 2023 Jan 27. 9(4): eadd4969

SUMOylation-mediated PSME3-20S proteasomal degradation of transcription factor CP2c is crucial for cell cycle progression.

Seung Han Son, Min Young Kim, Young Su Lim, Hyeon Cheol Jin, June Ho Shin, Jae Kyu Yi, Sungwoo Choi, Mi Ae Park, Ji Hyung Chae, Ho Chul Kang, Young Jin Lee, Vladimir N Uversky, Chul Geun Kim.

Transcription factor CP2c (also known as TFCP2, α-CP2, LSF, and LBP-1c) is involved in diverse ubiquitous and tissue/stage-specific cellular processes and in human malignancies such as cancer. Despite its importance, many fundamental regulatory mechanisms of CP2c are still unclear. Here, we uncover an unprecedented mechanism of CP2c degradation via a previously unidentified SUMO1/PSME3/20S proteasome pathway and its biological meaning. CP2c is SUMOylated in a SUMO1-dependent way, and SUMOylated CP2c is degraded through the ubiquitin-independent PSME3 (also known as REGγ or PA28)/20S proteasome system. SUMOylated PSME3 could also interact with CP2c to degrade CP2c via the 20S proteasomal pathway. Moreover, precisely timed degradation of CP2c via the SUMO1/PSME3/20S proteasome axis is required for accurate progression of the cell cycle. Therefore, we reveal a unique SUMO1-mediated uncanonical 20S proteasome degradation mechanism via the SUMO1/PSME3 axis involving mutual SUMO-SIM interaction of CP2c and PSME3, providing previously unidentified mechanistic insights into the roles of dynamic degradation of CP2c in cell cycle progression.

DOI: https://doi.org/10.1126/sciadv.add4969
FEBS J. 2023 Jan 27.

A glaucoma-associated OPTN polymorphism, M98K sensitizes retinal cells to endoplasmic reticulum stress and tumor necrosis factor α.

Zuberwasim Sayyad, Sreeram Kaveti, Debanjan Bhattacharjee, Dhiviya Vedagiri, Nishant Jain, Ghanshyam Swarup.

  Optineurin/OPTN polymorphism, M98K is associated with normal tension glaucoma in certain populations, and genetic evidence shows its interaction with tumor necrosis factor alpha (TNFα) polymorphism in causing glaucoma. Endoplasmic reticulum (ER) stress is also associated with glaucoma. We hypothesized that M98K-OPTN may sensitize retinal ganglion cells to various types of stress. To test this hypothesis, stable clones of a retinal cell line, 661W, expressing either wild-type (WT)-OPTN or M98K-OPTN were generated, and examined for their survival under various stress conditions. Compared to WT-OPTN expressing cells, M98K-OPTN expressing cells showed significantly lower cell survival and higher activation of caspase 3 and caspase 8 upon treatment with tunicamycin (an inducer of ER stress) or TNFα. Levels of ER stress sensors IRE1α, PERK and ATF6, were significantly higher in M98K-OPTN expressing cells. Tunicamycin treatment resulted in significantly higher induction of ER stress marker CHOP, and several other ER stress response genes regulated by IRE1α-XBP1, PERK-ATF4, and ATF6 pathways, in M98K-OPTN expressing cells. Splicing of XBP1, and ATF6 activation were higher in tunicamycin-treated M98K-OPTN expressing cells. Increased levels of PERK and IRE1α proteins in M98K-OPTN expressing cells were dependent on autophagy. Overall, our results show that M98K-OPTN sensitizes retinal cells to TNFα and ER stress-induced cell death. We also show that M98K-OPTN alters ER stress response signalling, which possibly enhances the sensitivity of retinal cells to ER stress. Our results provide support to the hypothesis that M98K-OPTN may cooperate with other genetic or environmental factors to cause retinal ganglion cell death associated with glaucoma.

Keywords:  ER stress; Glaucoma; Optineurin; RGC death; tumor necrosis factor α

DOI:  https://doi.org/10.1111/febs.16739
Elife. 2023 Jan 24. pii: e69521. [Epub ahead of print]12

Oncogenic PKA signaling increases c-MYC protein expression through multiple targetable mechanisms.

Gary K L Chan, Samantha Maisel, Yeonjoo C Hwang, Bryan C Pascual, Rebecca R B Wolber, Phuong Vu, Krushna C Patra, Mehdi Bouhaddou, Heidi L Kenerson, Huat C Lim, Donald Long, Raymond S Yeung, Praveen Sethupathy, Danielle L Swaney, Nevan J Krogan, Rigney E Turnham, Kimberly J Riehle, John D Scott, Nabeel Bardeesy, John D Gordan.

  Genetic alterations that activate protein kinase A (PKA) are found in many tumor types. Yet, their downstream oncogenic signaling mechanisms are poorly understood. We used global phosphoproteomics and kinase activity profiling to map conserved signaling outputs driven by a range of genetic changes that activate PKA in human cancer. Two signaling networks were identified downstream of PKA: RAS/MAPK components, and an Aurora Kinase A (AURKA) /glycogen synthase kinase (GSK3) sub-network with activity toward MYC oncoproteins. Findings were validated in two PKA-dependent cancer models: a novel, patient-derived fibrolamellar liver cancer (FLC) line that expresses a DNAJ-PKAc fusion, and a PKA-addicted melanoma model with a mutant Type I PKA regulatory subunit. We identify PKA signals that can influence both de novo translation and stability of the proto-oncogene c-MYC. However, the primary mechanism of PKA effects on MYC in our cell models was translation and could be blocked with the eIF4A inhibitor zotatifin. This compound dramatically reduced c-MYC expression and inhibited FLC cell line growth in vitro. Thus, targeting PKA effects on translation is a potential treatment strategy for FLC and other PKA-driven cancers.

Keywords:  cancer biology; human

DOI:  https://doi.org/10.7554/eLife.69521
Br J Cancer. 2023 Jan 21.

Immunoproteasome inhibition prevents progression of castration-resistant prostate cancer.

Jun Li, Nan Liu, Hong Zhou, Peng Xian, Yanping Song, Xianli Tang, Yuan Li, Michael Basler.

BACKGROUND: Castration-resistant prostate cancer (CRPC) is refractory to hormone treatment. This study aims to explore the effect and underlying mechanisms of immunoproteasome inhibition, a novel immunotherapy, on the progression of CRPC.METHODS: The immunoproteasome subunit LMP7 was silenced by using gene knockout or inhibited by the epoxyketone inhibitor ONX 0914 in a mouse CRPC tumour graft model and in interferon-γ-pretreated human CRPC cell lines in vitro.
RESULTS: CRPC tissues reveal a significant "tumour-elicited" Th17-type inflammatory response which induces immunoproteasome subunit expression. LMP7 deficiency in host mice or in CRPC tumour grafts had no effect on the "tumour-elicited" Th17-type inflammatory response and tumour progression. However, the selective LMP7 inhibitor ONX 0914 strongly suppressed the "tumour-elicited" Th17-type inflammatory response and CRPC tumour progression. Treatment of wild-type mice receiving LMP7-deficient CRPC tumour grafts with ONX 0914 further suggested that immunoproteasome inhibition prevents CRPC progression through suppressing IL-17-induced angiogenesis and epithelial-mesenchymal transition via inactivation of COX-2/VEGF-A signalling and β-catenin/Snail signalling. Treatment of LMP7-deficient mice receiving wild-type CRPC tumour grafts with ONX 0914 and inhibition of LMP7 in PC3 and 22Rv.1 cells with ONX 0914 showed that immunoproteasome inhibition also prevents CRPC progression through inducing CRPC cell apoptosis via activation of the unfolded protein response.
CONCLUSIONS: We define a critical role of the immunoproteasome in CRPC and propose immunoproteasome inhibition as a promising therapeutic approach to suppress CRPC progression.

DOI: https://doi.org/10.1038/s41416-022-02129-2
J Cell Sci. 2023 Jan 25. pii: jcs.259788. [Epub ahead of print]

Lamin A/C phosphorylation at serine 22 is a conserved heat shock response to regulate nuclear adaptation during stress.

Laura Virtanen, Emilia Holm, Mona Halme, Gun West, Fanny Lindholm, Josef Gullmets, Juho Irjala, Tiina Heliö, Artur Padzik, Annika Meinander, John E Eriksson, Pekka Taimen.

  The heat shock (HS) response is crucial for cell survival in harmful environments. Nuclear lamin A/C (LA/C), encoded by LMNA gene, contributes towards altered gene expression during HS, but the underlying mechanisms are poorly understood. Here we show that upon HS, LA/C is reversibly phosphorylated at Ser22 in concert with HSF1 activation in human cells, mouse cells and D. melanogaster in vivo. Consequently, the phosphorylation facilitated nucleoplasmic localization of LA/C and nuclear sphericity in response to HS. Interestingly, LA/C knock-out cells showed deformed nuclei after HS and were rescued by ectopic expression of wild-type LA, but not by a phosphomimetic (S22D) LA mutant. Furthermore, HS triggered concurrent downregulation of lamina-associated protein 2α (Lap2α) in wild-type LA/C expressing cells but a similar response was perturbed in LA/C knock-out cells and in LMNA mutant patient fibroblasts which showed impaired cell cycle arrest under HS and compromised survival at the recovery. Taken together, our results suggest that the altered phosphorylation stoichiometry of LA/C provides an evolutionary conserved mechanism to regulate lamina structure and serve nuclear adaptation and cell survival during HS.

Keywords:  Heat shock; Heat shock response; Lamin A/C; Lap2α; Phosphorylation

DOI:  https://doi.org/10.1242/jcs.259788
Cell Death Discov. 2023 Jan 23. 9(1): 23

NEDD8-conjugating enzyme E2s: critical targets for cancer therapy.

Lisha Zhou, Xiongzhi Lin, Jin Zhu, Luyi Zhang, Siyuan Chen, Hui Yang, Lijun Jia, Baofu Chen.

NEDD8-conjugating enzymes, E2s, include the well-studied ubiquitin-conjugating enzyme E2 M (UBE2M) and the poorly characterized ubiquitin-conjugating enzyme E2 F (UBE2F). UBE2M and UBE2F have distinct and prominent roles in catalyzing the neddylation of Cullin or non-Cullin substrates. These enzymes are overexpressed in various malignancies, conferring a worse overall survival. Targeting UBE2M to influence tumor growth by either modulating several biological responses of tumor cells (such as DNA-damage response, apoptosis, or senescence) or regulating the anti-tumor immunity holds strong therapeutic potential. Multiple inhibitors that target the interaction between UBE2M and defective cullin neddylation protein 1 (DCN1), a co-E3 for neddylation, exhibit promising anti-tumor effects. By contrast, the potential benefits of targeting UBE2F are still to be explored. It is currently reported to inhibit apoptosis and then induce cell growth; hence, targeting UBE2F serves as an effective chemo-/radiosensitizing strategy by triggering apoptosis. This review highlights the most recent advances in the roles of UBE2M and UBE2F in tumor progression, indicating these E2s as two promising anti-tumor targets.

DOI: https://doi.org/10.1038/s41420-023-01337-w