bims-unfpre 2022-11-13 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2022‒11‒13
eleven papers selected by
Susan Logue
University of Manitoba

Cancer cell-intrinsic XBP1 drives immunosuppressive reprogramming of intratumoral myeloid cells by promoting cholesterol production.
Prx1 Regulates Thapsigargin-Mediated UPR Activation and Apoptosis.
Enteroviruses Manipulate the Unfolded Protein Response through Multifaceted Deregulation of the Ire1-Xbp1 Pathway.
Endoplasmic Reticulum Stress in Chronic Obstructive Pulmonary Disease: Mechanisms and Future Perspectives.
Dissociation of ERMES clusters plays a key role in attenuating the endoplasmic reticulum stress.
Platelet derived growth factor promotes the recovery of traumatic brain injury by inhibiting endoplasmic reticulum stress and autophagy-mediated pyroptosis.
Inhibition of USP1 activates ER stress through Ubi-protein aggregation to induce autophagy and apoptosis in HCC.
PRP-1, a toll-like receptor ligand, upregulates the unfolded protein response in human chondrosarcoma cells.
Integration of ER protein quality control mechanisms defines β-cell function and ER architecture.
RTCB Complex Regulates Stress-Induced tRNA Cleavage.
The Proteostasis Network: A Global Therapeutic Target for Neuroprotection after Spinal Cord Injury.

Cell Metab. 2022 Nov 02. pii: S1550-4131(22)00461-2. [Epub ahead of print]

Cancer cell-intrinsic XBP1 drives immunosuppressive reprogramming of intratumoral myeloid cells by promoting cholesterol production.

Zaili Yang, Yazhen Huo, Shixin Zhou, Jingya Guo, Xiaotu Ma, Tao Li, Congli Fan, Likun Wang.

  A hostile microenvironment in tumor tissues disrupts endoplasmic reticulum homeostasis and induces the unfolded protein response (UPR). A chronic UPR in both cancer cells and tumor-infiltrating leukocytes could facilitate the evasion of immune surveillance. However, how the UPR in cancer cells cripples the anti-tumor immune response is unclear. Here, we demonstrate that, in cancer cells, the UPR component X-box binding protein 1 (XBP1) favors the synthesis and secretion of cholesterol, which activates myeloid-derived suppressor cells (MDSCs) and causes immunosuppression. Cholesterol is delivered in the form of small extracellular vesicles and internalized by MDSCs through macropinocytosis. Genetic or pharmacological depletion of XBP1 or reducing the tumor cholesterol content remarkably decreases MDSC abundance and triggers robust anti-tumor responses. Thus, our data unravel the cell-non-autonomous role of XBP1/cholesterol signaling in the regulation of tumor growth and suggest its inhibition as a useful strategy for improving the efficacy of cancer immunotherapy.

Keywords:  ER stress; HMGCR; IRE1α; MDSC; XBP1; cancer immunosuppression; cholesterol; macropinocytosis; small extracellular vesicle; unfolded protein response

DOI:  https://doi.org/10.1016/j.cmet.2022.10.010
Genes (Basel). 2022 Nov 04. pii: 2033. [Epub ahead of print]13(11):

Prx1 Regulates Thapsigargin-Mediated UPR Activation and Apoptosis.

Eun-Kyung Kim, Yosup Kim, Jun Young Yang, Ho Hee Jang.

  Endoplasmic reticulum (ER) stress activates the unfolded protein response (UPR) signaling via the accumulation of unfolded and misfolded proteins. ER stress leads to the production of reactive oxygen species (ROS), which are necessary to maintain redox homeostasis in the ER. Although peroxiredoxin 1 (Prx1) is an antioxidant enzyme that regulates intracellular ROS levels, the link between Prx1 and ER stress remains unclear. In this study, we investigated the role of Prx1 in X-box binding protein 1 (XBP-1) activation, the C/EBP homologous protein (CHOP) pathway, and apoptosis in response to ER stress. We observed that Prx1 overexpression inhibited the nuclear localization of XBP-1 and the expression of XBP-1 target genes and CHOP after thapsigargin (Tg) treatment to induce ER stress. In addition, Prx1 inhibited apoptosis and ROS production during ER stress. The ROS scavenger inhibited ER stress-induced apoptosis but did not affect XBP-1 activation and CHOP expression. Therefore, the biological role of Prx1 in ER stress may have important implications for ER stress-related diseases.

Keywords:  apoptosis; endoplasmic reticulum stress; peroxiredoxin; reactive oxygen species; unfolded protein response signaling

DOI:  https://doi.org/10.3390/genes13112033
Viruses. 2022 Nov 10. pii: 2486. [Epub ahead of print]14(11):

Enteroviruses Manipulate the Unfolded Protein Response through Multifaceted Deregulation of the Ire1-Xbp1 Pathway.

Anna Shishova, Ilya Dyugay, Ksenia Fominykh, Victoria Baryshnikova, Alena Dereventsova, Yuriy Turchenko, Anna A Slavokhotova, Yury Ivin, Sergey E Dmitriev, Anatoly Gmyl.

  Many viruses are known to trigger endoplasmic reticulum (ER) stress in host cells, which in turn can develop a protective unfolded protein response (UPR). Depending on the conditions, the UPR may lead to either cell survival or programmed cell death. One of three UPR branches involves the upregulation of Xbp1 transcription factor caused by the unconventional cytoplasmic splicing of its mRNA. This process is accomplished by the phosphorylated form of the endoribonuclease/protein kinase Ire1/ERN1. Here, we show that the phosphorylation of Ire1 is up-regulated in HeLa cells early in enterovirus infection but down-regulated at later stages. We also find that Ire1 is cleaved in poliovirus- and coxsackievirus-infected HeLa cells 4-6 h after infection. We further show that the Ire1-mediated Xbp1 mRNA splicing is repressed in infected cells in a time-dependent manner. Thus, our results demonstrate the ability of enteroviruses to actively modulate the Ire1-Xbp1 host defensive pathway by inducing phosphorylation and proteolytic cleavage of the ER stress sensor Ire1, as well as down-regulating its splicing activity. Inactivation of Ire1 could be a novel mode of the UPR manipulation employed by viruses to modify the ER stress response in the infected cells.

Keywords:  ER stress; Ire1 proteolysis; Ire1-Xbp1 pathway; coxsackievirus; picornavirus; poliovirus; unfolded protein response

DOI:  https://doi.org/10.3390/v14112486
Biomolecules. 2022 Nov 04. pii: 1637. [Epub ahead of print]12(11):

Endoplasmic Reticulum Stress in Chronic Obstructive Pulmonary Disease: Mechanisms and Future Perspectives.

Yue Yu, Ailin Yang, Ganggang Yu, Haoyan Wang.

  The endoplasmic reticulum (ER) is an integral organelle for maintaining protein homeostasis. Multiple factors can disrupt protein folding in the lumen of the ER, triggering ER stress and activating the unfolded protein response (UPR), which interrelates with various damage mechanisms, such as inflammation, apoptosis, and autophagy. Numerous studies have linked ER stress and UPR to the progression of chronic obstructive pulmonary disease (COPD). This review focuses on the mechanisms of other cellular processes triggered by UPR and summarizes drug intervention strategies targeting the UPR pathway in COPD to explore new therapeutic approaches and preventive measures for COPD.

Keywords:  apoptosis; autophagy; chronic obstructive pulmonary disease; endoplasmic reticulum stress; inflammation; therapeutic

DOI:  https://doi.org/10.3390/biom12111637
iScience. 2022 Nov 18. 25(11): 105362

Dissociation of ERMES clusters plays a key role in attenuating the endoplasmic reticulum stress.

Yuriko Kakimoto-Takeda, Rieko Kojima, Hiroya Shiino, Manatsu Shinmyo, Kazuo Kurokawa, Akihiko Nakano, Toshiya Endo, Yasushi Tamura.

  In yeast, ERMES, which mediates phospholipid transport between the ER and mitochondria, forms a limited number of oligomeric clusters at ER-mitochondria contact sites in a cell. Although the number of the ERMES clusters appears to be regulated to maintain proper inter-organelle phospholipid trafficking, its underlying mechanism and physiological relevance remain poorly understood. Here, we show that mitochondrial dynamics control the number of ERMES clusters. Moreover, we find that ER stress causes dissociation of the ERMES clusters independently of Ire1 and Hac1, canonical ER-stress response pathway components, leading to a delay in the phospholipid transport from the ER to mitochondria. Our biochemical and genetic analyses strongly suggest that the impaired phospholipid transport contributes to phospholipid accumulation in the ER, expanding the ER for ER stress attenuation. We thus propose that the ERMES dissociation constitutes an overlooked pathway of the ER stress response that operates in addition to the canonical Ire1/Hac1-dependent pathway.

Keywords:  Biological sciences; Cell biology; Functional aspects of cell biology

DOI:  https://doi.org/10.1016/j.isci.2022.105362
Front Pharmacol. 2022 ;13 862324

Platelet derived growth factor promotes the recovery of traumatic brain injury by inhibiting endoplasmic reticulum stress and autophagy-mediated pyroptosis.

Fangfang Wu, Renkan Zhang, Weiyang Meng, Lei Liu, Yingdan Tang, Leilei Lu, Leilei Xia, Hongyu Zhang, Zhiguo Feng, Daqing Chen.

  Autophagy and endoplasmic reticulum stress (ER stress) are important in numerous pathological processes in traumatic brain injury (TBI). Growing evidence has indicated that pyroptosis-associated inflammasome is involved in the pathogenesis of TBI. Platelet derived growth factor (PDGF) has been reported to be as a potential therapeutic drug for neurological diseases. However, the roles of PDGF, autophagy and ER stress in pyroptosis have not been elucidated in the TBI. This study investigated the roles of ER stress and autophagy after TBI at different time points. We found that the ER stress and autophagy after TBI were inhibited, and the expressions of pyroptosis-related proteins induced by TBI, including NLRP3, Pro-Caspase1, Caspase1, GSDMD, GSDMD P30, and IL-18, were decreased upon PDGF treatment. Moreover, the rapamycin (RAPA, an autophagy activator) and tunicamycin (TM, an ER stress activator) eliminated the PDGF effect on the pyroptosis after TBI. Interestingly, the sodium 4-phenylbutyrate (4-PBA, an ER stress inhibitor) suppressed autophagy but 3-methyladenine (3-MA, an autophagy inhibitor) not for ER stress. The results revealed that PDGF improved the functional recovery after TBI, and the effects were markedly reversed by TM and RAPA. Taken together, this study provides a new insight that PDGF is a potential therapeutic strategy for enhancing the recovery of TBI.

Keywords:  PDGF; PDGF ameliorates traumatic brain injury; autophagy; er stress; pyroptosis; traumatic brain injury

DOI:  https://doi.org/10.3389/fphar.2022.862324
Cell Death Dis. 2022 Nov 10. 13(11): 951

Inhibition of USP1 activates ER stress through Ubi-protein aggregation to induce autophagy and apoptosis in HCC.

Longhao Wang, Tao Hu, Zhibo Shen, Yuanyuan Zheng, Qishun Geng, Lifeng Li, Beibei Sha, Miaomiao Li, Yaxin Sun, Yongjun Guo, Wenhua Xue, Dan Xuan, Ping Chen, Jie Zhao.

The deubiquitinating enzyme USP1 (ubiquitin-specific protease 1) plays a role in the progression of various tumors, emerging as a potential therapeutic target. This study aimed to determine the role of USP1 as a therapeutic target in hepatocellular carcinoma (HCC). We detected USP1 expression in the tumor and adjacent tissues of patients with HCC using immunohistochemical staining. We evaluated the effect of the USP1 inhibitor ML-323 on HCC cell proliferation and cell cycle using a CCK-8 cell-counting kit and plate cloning assays, and propidium iodide, respectively. Apoptosis was detected by annexin V-FITC/Propidium Iodide (PI) staining and caspase 3 (casp3) activity. Transmission electron microscopy and LC3B immunofluorescence were used to detect autophagy. Western blotting was used to detect the accumulation of ubiquitinated proteins, the expression of endoplasmic reticulum (ER) stress-related proteins, and the AMPK-ULK1/ATG13 signaling pathway. We demonstrated that ML-323 inhibits the growth of HCC cells and induces G1 phase cell cycle arrest by regulating cyclin expression. ML-323 treatment resulted in the accumulation of ubiquitinated proteins, induced ER stress, and triggered Noxa-dependent apoptosis, which was regulated by the Activating Transcription Factor 4(ATF4). Moreover, active ER stress induces protective autophagy by increasing AMPK phosphorylation; therefore, we inhibited ER stress using 4-Phenylbutyric acid (4-PBA), which resulted in ER stress reduction, apoptosis, and autophagy in ML-323-treated HCC cells. In addition, blocking autophagy using the AMPK inhibitor compound C (CC), chloroquine (CQ), or bafilomycin A1 (BafA1) enhanced the cytotoxic effect of ML-323. Our findings revealed that targeting USP1 may be a potential strategy for the treatment of HCC.

DOI: https://doi.org/10.1038/s41419-022-05341-3
Cancer Treat Res Commun. 2022 Sep 27. pii: S2468-2942(22)00135-6. [Epub ahead of print]33 100644

PRP-1, a toll-like receptor ligand, upregulates the unfolded protein response in human chondrosarcoma cells.

Karina Galoian, Victoria Dahl, Andres Perez, Carina Denny, Beatrice Becker, Anil Sedani, Alexandra Moran, Daniel Martinez, Aaron Hoyt, Jeffrey Brown.

  BACKGROUND: Previous studies showed that proline-rich polypeptide (PRP-1) is a ligand for innate immunity toll-like receptors (TLR), and an inhibitor of the mammalian target of rapamycin complex 1 (mTORC1) which induces the death of chondrosarcoma cancer stem cells (CSC). The aim of this study was to investigate the effect of PRP-1 on the regulation of unfolded protein response (UPR) in human chondrosarcoma cells.MATERIALS AND METHODS: Lysates were prepared from a monolayer (bulk or ALDHhigh population), or spheroids chondrosarcoma cell cultures and treated with PRP-1 or control, followed by protein levels quantification by western blotting and mRNA expression by RT-qPCR of protein-RNA-like endoplasmic reticulum kinase (PERK), eukaryotic translation initiation factor 2α (eIF2α), activating transcription factor 4 (ATF4), CCAAT-enhancer-binding protein homologous protein (CHOP), activating transcription factor 6 (ATF6), inositol-requiring enzyme 1 (IRE1α), and X-box binding protein (XBP1).
RESULTS: The PRP-1 has been shown to increase the expression of PERK, eIF2α, ATF4, CHOP, ATF6, IRE1α, and XBP1, on both protein and mRNA levels.
CONCLUSION: PRP-1 activated UPR branches in monolayer, spheroid, and stem cell populations of human chondrosarcoma.

Keywords:  Cellular stress; Chondrosarcoma; Proline-rich polypeptide (PRP-1); Toll-like receptors; Unfolded protein response

DOI:  https://doi.org/10.1016/j.ctarc.2022.100644
J Clin Invest. 2022 Nov 08. pii: e163584. [Epub ahead of print]

Integration of ER protein quality control mechanisms defines β-cell function and ER architecture.

Neha Shrestha, Mauricio Torres, Jason Zhang, You Lu, Leena Haataja, Rachel B Reinert, Jeffrey Knupp, Yu-Jie Chen, Gunes Parlakgul, Ana Paula Arruda, Billy Tsai, Peter Arvan, Ling Qi.

  Three principal ER quality-control mechanisms, namely, unfolded protein response (UPR), ER-associated degradation (ERAD) and ER-phagy are each important for the maintenance of ER homeostasis, yet how they are integrated to regulate ER homeostasis and organellar architecture in vivo is largely unclear. Here we report intricate crosstalk among the three pathways, centered around the SEL1L-HRD1 protein complex of ERAD, in the regulation of organellar organization in β-cells. SEL1L-HRD1 ERAD deficiency in β-cells triggers activation of autophagy via IRE1α [an endogenous ERAD substrate]. In the absence of functional SEL1L-HRD1 ERAD, proinsulin is retained in the ER as high molecular weight conformers, which are subsequently cleared via ER-phagy. A combined loss of both SEL1L and autophagy in β-cells leads to diabetes in mice shortly after weaning, with premature death by ~11 weeks of age, associated with marked ER retention of proinsulin and β-cell loss. Using focus-ion beam scanning electron microscopy (FIB-SEM) powered by deep-learning automated image segmentation and 3D reconstruction, our data demonstrate a profound organellar restructuring with a massive expansion of ER volume and network in β-cells lacking both SEL1L and autophagy. These data reveal at an unprecedented detail the intimate crosstalk among the three ER quality-control mechanisms in the dynamic regulation of organellar architecture and β-cell function.

Keywords:  Autophagy; Cell Biology; Diabetes; Metabolism; Protein misfolding

DOI:  https://doi.org/10.1172/JCI163584
Int J Mol Sci. 2022 Oct 28. pii: 13100. [Epub ahead of print]23(21):

RTCB Complex Regulates Stress-Induced tRNA Cleavage.

Yasutoshi Akiyama, Yoshika Takenaka, Tomoko Kasahara, Takaaki Abe, Yoshihisa Tomioka, Pavel Ivanov.

  Under stress conditions, transfer RNAs (tRNAs) are cleaved by stress-responsive RNases such as angiogenin, generating tRNA-derived RNAs called tiRNAs. As tiRNAs contribute to cytoprotection through inhibition of translation and prevention of apoptosis, the regulation of tiRNA production is critical for cellular stress response. Here, we show that RTCB ligase complex (RTCB-LC), an RNA ligase complex involved in endoplasmic reticulum (ER) stress response and precursor tRNA splicing, negatively regulates stress-induced tiRNA production. Knockdown of RTCB significantly increased stress-induced tiRNA production, suggesting that RTCB-LC negatively regulates tiRNA production. Gel-purified tiRNAs were repaired to full-length tRNAs by RtcB in vitro, suggesting that RTCB-LC can generate full length tRNAs from tiRNAs. As RTCB-LC is inhibited under oxidative stress, we further investigated whether tiRNA production is promoted through the inhibition of RTCB-LC under oxidative stress. Although hydrogen peroxide (H2O2) itself did not induce tiRNA production, it rapidly boosted tiRNA production under the condition where stress-responsive RNases are activated. We propose a model of stress-induced tiRNA production consisting of two factors, a trigger and booster. This RTCB-LC-mediated boosting mechanism may contribute to the effective stress response in the cell.

Keywords:  RTCB ligase complex; angiogenin; oxidative stress; tRNA; tiRNAs

DOI:  https://doi.org/10.3390/ijms232113100
Cells. 2022 Oct 22. pii: 3339. [Epub ahead of print]11(21):

The Proteostasis Network: A Global Therapeutic Target for Neuroprotection after Spinal Cord Injury.

Scott R Whittemore, Sujata Saraswat Ohri, Michael D Forston, George Z Wei, Michal Hetman.

  Proteostasis (protein homeostasis) is critical for cellular as well as organismal survival. It is strictly regulated by multiple conserved pathways including the ubiquitin-proteasome system, autophagy, the heat shock response, the integrated stress response, and the unfolded protein response. These overlapping proteostasis maintenance modules respond to various forms of cellular stress as well as organismal injury. While proteostasis restoration and ultimately organism survival is the main evolutionary driver of such a regulation, unresolved disruption of proteostasis may engage pro-apoptotic mediators of those pathways to eliminate defective cells. In this review, we discuss proteostasis contributions to the pathogenesis of traumatic spinal cord injury (SCI). Most published reports focused on the role of proteostasis networks in acute/sub-acute tissue damage post-SCI. Those reports reveal a complex picture with cell type- and/or proteostasis mediator-specific effects on loss of neurons and/or glia that often translate into the corresponding modulation of functional recovery. Effects of proteostasis networks on such phenomena as neuro-repair, post-injury plasticity, as well as systemic manifestations of SCI including dysregulation of the immune system, metabolism or cardiovascular function are currently understudied. However, as potential interventions that target the proteostasis networks are expected to impact many cell types across multiple organ systems that are compromised after SCI, such therapies could produce beneficial effects across the wide spectrum of highly variable human SCI.

Keywords:  ER stress; cell death; neurons; neuroprotection; neurotrauma; oligodendrocytes; proteostasis; spinal cord injury; white matter

DOI:  https://doi.org/10.3390/cells11213339