bims-apauto 2022-04-24 papers

Issue of 2022–04–24
eight papers selected by
Su Hyun Lee, Seoul National University

Mol Cell. 2022 Apr 21. pii: S1097-2765(22)00156-3. [Epub ahead of print]82(8): 1492-1500

The endoplasmic reticulum (ER) is a hotspot for many essential cellular functions. The ER membrane is highly dynamic, which affects many cellular processes that take place within the ER. One such process is ER-phagy, a selective degradation of ER fragments (including membranes and luminal content), which serves to preserve the size of ER while adapting its morphology under basal and stress conditions. In order to be degraded, the ER undergoes selective fragmentation facilitated by specialized ER-shaping proteins that also act as ER-phagy receptors. Their ability to sense and induce membrane curvature, as well as to bridge the ER with autophagy machinery, allows for a successful ER fragmentation and delivery of these fragments to the lysosome for degradation and recycling. In this review, we provide insights into ER-phagy from the perspective of membrane remodeling. We highlight the importance of ER membrane dynamics during ER-phagy and emphasize how its dysregulation reflects on human physiology and pathology.

DOI: https://doi.org/10.1016/j.molcel.2022.02.018

Mol Cell. 2022 Apr 21. pii: S1097-2765(22)00253-2. [Epub ahead of print]82(8): 1604-1604.e1

SnapShot: Organelle degradation.

Noboru Mizushima.

Organelles are continuously turned over as part of cellular homeostasis and adaptation. Most organelles, even including the nucleus, are degraded by lysosomes via different pathways, such as macroautophagy, microautophagy, organelle-derived vesicle degradation, and crinophagy. In some specific cases-for example, in lens fiber cells-organelles are degraded by cytosolic phospholipases. To view this SnapShot, open or download the PDF.

DOI: https://doi.org/10.1016/j.molcel.2022.03.015

Mol Cell. 2022 Apr 21. pii: S1097-2765(22)00261-1. [Epub ahead of print]82(8): 1514-1527

Autophagy in cancer cell remodeling and quality control.

Grace A Hernandez, Rushika M Perera.

As one of the two highly conserved cellular degradation systems, autophagy plays a critical role in regulation of protein, lipid, and organelle quality control and cellular homeostasis. This evolutionarily conserved pathway singles out intracellular substrates for elimination via encapsulation within a double-membrane vesicle and delivery to the lysosome for degradation. Multiple cancers disrupt normal regulation of autophagy and hijack its degradative ability to remodel their proteome, reprogram their metabolism, and adapt to environmental challenges, making the autophagy-lysosome system a prime target for anti-cancer interventions. Here, we discuss the roles of autophagy in tumor progression, including cancer-specific mechanisms of autophagy regulation and the contribution of tumor and host autophagy in metabolic regulation, immune evasion, and malignancy. We further discuss emerging proteomics-based approaches for systematic profiling of autophagosome-lysosome composition and contents. Together, these approaches are uncovering new features and functions of autophagy, leading to more effective strategies for targeting this pathway in cancer.

Keywords: autophagy; cancer; lysosome; quality control; remodeling

DOI: https://doi.org/10.1016/j.molcel.2022.03.023

Mol Cell. 2022 Apr 21. pii: S1097-2765(22)00313-6. [Epub ahead of print]82(8): 1390-1397

Quality Control: Maintaining molecular order and preventing cellular chaos.

Sonya Neal, Fumiaki Ohtake, Ana Maria Cuervo, Ramanujan S Hegde, Ursula Jakob, Michael Lazarou, Wendy V Gilbert, Zhijian J Chen, Sharon A Tooze, James E Haber, Kylie J Walters, F Ulrich Hartl.

We asked experts from different fields-from genome maintenance and proteostasis to organelle degradation via ubiquitin and autophagy-"What does quality control mean to you?" Despite their diverse backgrounds, they converge on and discuss the importance of continuous quality control at all levels, context, communication, timing, decisions on whether to repair or remove, and the significance of dysregulated quality control in disease.

DOI: https://doi.org/10.1016/j.molcel.2022.04.002

Autophagy. 2022 Apr 18. 1-9

Acetylation in the regulation of autophagy.

Yinfeng Xu, Wei Wan.

Post-translational modifications, such as phosphorylation, ubiquitination and acetylation, play crucial roles in the regulation of autophagy. Acetylation has emerged as an important regulatory mechanism for autophagy. Acetylation regulates autophagy initiation and autophagosome formation by targeting core components of the ULK1 complex, the BECN1-PIK3C3 complex, and the LC3 lipidation system. Recent studies have shown that acetylation occurs on the key proteins participating in autophagic cargo assembly and autophagosome-lysosome fusion, such as SQSTM1/p62 and STX17. In addition, acetylation controls autophagy at the transcriptional level by targeting histones and the transcription factor TFEB. Here, we review the current knowledge on acetylation of autophagy proteins and their regulations and functions in the autophagy pathway with focus on recent findings.Abbreviations : ACAT1: acetyl-CoA acetyltransferase 1; ACSS2: acyl-CoA synthetase short chain family member 2; AMPK: AMP-activated protein kinase; ATG: autophagy-related; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CCAR2/DBC1: cell cycle and apoptosis regulator 2; BECN1: beclin 1; CMA: chaperone-mediated autophagy; CREBBP/CBP: CREB binding protein; EP300/p300: E1A binding protein p300; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GSK3: glycogen synthase kinase 3; HDAC6: histone deacetylase 6; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; KAT2A/GCN5: lysine acetyltransferase 2A; KAT2B/PCAF: lysine acetyltransferase 2B; KAT5/TIP60: lysine acetyltransferase 5; KAT8/MOF: lysine acetyltransferase 8; LAMP2A: lysosomal associated membrane protein 2A; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; NBR1: NBR1 autophagy cargo receptor; OPTN: optineurin; PD: Parkinson disease; PE: phosphatidylethanolamine; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PKM2: pyruvate kinase M1/2; PtdIns3P: phosphatidylinositol-3-phosphate; PTM: post-translational modification; RB1CC1/FIP200: RB1 inducible coiled-coil 1; RUBCN/Rubicon: rubicon autophagy regulator; RUBCNL/Pacer: rubicon like autophagy enhancer; SIRT1: sirtuin 1; SNAP29: synaptosome associated protein 29; SNARE: soluble N-ethylamide-sensitive factor attachment protein receptor; SQSTM1/p62: sequestosome 1; STX17: syntaxin 17; TFEB: transcription factor EB; TP53/p53: tumor protein p53; TP53INP2/DOR: tumor protein p53 inducible nuclear protein 2; UBA: ubiquitin-associated; ULK1: unc-51 like autophagy activating kinase 1; VAMP8: vesicle associated membrane protein 8; WIPI2: WD repeat domain, phosphoinositide interacting 2.

Keywords: Acetylation; acetyltransferase; autophagy; deacetylase; post-translational modification

DOI: https://doi.org/10.1080/15548627.2022.2062112

Autophagy. 2022 Apr 19. 1-3

FKBP5/FKBP51 on weight watch: central FKBP5 links regulatory WIPI protein networks to autophagy and metabolic control.

Thomas Bajaj, Alexander S Häusl, Mathias V Schmidt, Nils C Gassen.

Stress and changes in energy stores are perceived by hormone- and nutrient-sensing nuclei of the hypothalamus, which orchestrate an adaptive physiological body response to maintain homeostasis. Macroautophagy/autophagy is a fundamental lysosomal degradation system contributing to preservation of proteome balance and metabolic homeostasis. Its dysregulation is linked to diverse human pathologies, including neuropsychiatric and metabolic disorders. Autophagy is coordinated by cellular nutrient sensors, including AMPK and MTORC1 that interact with WIPI proteins. Studies suggest that WDR45/WIPI4 interacts with the stress-sensitive co-chaperone FKBP5/FKBP51, which has emerged as a key autophagy scaffold. However, the impact of FKBP5 on autophagy signaling in response to metabolic challenges, such as a high-fat diet, is elusive. Therefore, we manipulated FKBP5 in the mediobasal hypothalamus (MBH) and studied autophagy signaling and protein interactions in their physiological context. We identified FKBP5 as a scaffold of the STK11/LKB1-AMPK complex with WDR45/WIPI4 and TSC2 with WDR45B/WIPI3 in response to metabolic challenges, positioning FKBP5 in major nutrient-sensing and autophagy-regulating networks. Intriguingly, we could demonstrate that FKBP5 deletion in the MBH strongly induces obesity, whereas its overexpression protects against high-fat diet-induced obesity. Our findings suggest a crucial regulatory and adaptive function of FKBP5-regulated autophagy within the MBH in response to metabolic challenges.Abbreviations: AKT: thymoma viral proto-oncogene; AMPK: AMP-activated protein kinase; BECN1: beclin 1, autophagy related; eWAT: epididymal white adipose tissue; FKBP5/FKBP51: FK506 binding protein 5; KO, knockout; MBH, mediobasal hypothalamus; MTORC1, mechanistic target of rapamycin kinase complex 1; p: phosphorylated; PHLPP: PH domain and leucine rich repeat protein phosphatase; RPS6KB/p70S6K: ribosomal protein S6 kinase; SKP2: S-phase kinase-associated protein 2; SM: soleus muscle; SQSTM1/p62, sequestosome 1; STK11/LKB1: serine/threonine kinase 11; TSC: TSC complex; ULK1: unc-51 like kinase 1; WIPI: WD repeat domain, phosphoinositide interacting; WT: wild type.

Keywords: AMPK; FKBP5/FKBP51; WIPI; autophagy; metabolic stress

DOI: https://doi.org/10.1080/15548627.2022.2063006

J Cell Biol. 2022 Jun 06. pii: e202110151. [Epub ahead of print]221(6):

Secretory autophagy maintains proteostasis upon lysosome inhibition.

Tina A Solvik, Tan A Nguyen, Yu-Hsiu Tony Lin, Timothy Marsh, Eric J Huang, Arun P Wiita, Jayanta Debnath, Andrew M Leidal.

The endolysosome system plays central roles in both autophagic degradation and secretory pathways, including the release of extracellular vesicles and particles (EVPs). Although previous work reveals important interconnections between autophagy and EVP-mediated secretion, our understanding of these secretory events during endolysosome inhibition remains incomplete. Here, we delineate a secretory autophagy pathway upregulated in response to endolysosomal inhibition, which mediates EVP-associated release of autophagic cargo receptors, including p62/SQSTM1. This secretion is highly regulated and dependent on multiple ATGs required for autophagosome formation, as well as the small GTPase Rab27a. Furthermore, disrupting autophagosome maturation, either via genetic inhibition of autophagosome-to-autolysosome fusion or expression of SARS-CoV-2 ORF3a, is sufficient to induce EVP secretion of autophagy cargo receptors. Finally, ATG-dependent EVP secretion buffers against the intracellular accumulation of autophagy cargo receptors when classical autophagic degradation is impaired. Thus, we propose secretory autophagy via EVPs functions as an alternate route to clear sequestered material and maintain proteostasis during endolysosomal dysfunction or impaired autophagosome maturation.

DOI: https://doi.org/10.1083/jcb.202110151

Life Sci. 2022 Apr 19. pii: S0024-3205(22)00252-1. [Epub ahead of print] 120552

Cancer cell's internal and external warriors: Autophagosomes and exosomes.

V A Subramanian, Ravindra Bairwa, Pradeep Sharma, Bhawana Bissa.

"That survival instinct, that will to live, that need to get back to life again, is more powerful than any consideration of taste, decency, politeness, manners, civility, anything. It's such a powerful force." This quote by famous director Danny Boyle is a perfect analogy to describe the cancer cell's inexhaustible drive to persist against all odds. In order to adapt to a hostile environment, the cancer cells rely on multiple mechanisms including immune escape, epithelial to mesenchymal transition, angiogenesis, extravasation, autophagy, exosome release among others. Cancer cells depute their internal and external warriors, autophagosomes and exosomes, to dwell in the belligerent tumor microenvironment. It is quite reasonable for a cancer cell, striving to survive, to invest in pathways that will provide the maximum advantage. Autophagy is an important cellular degradation pathway, while the exosome pathway provides an alternative cargo disposal mechanism to maintain the homeostasis and cell survival. While autophagic degradation provides the essential nutrients to rapidly dividing cells, exosomal secretion ensures that the tumor microenvironment is attuned to accommodate the swiftly expanding tumor mass. Studies have revealed that exosomes secreted by cancer cells can modulate autophagy in recipient cells, while autophagy can influence the biogenesis of exosomes. Autophagy and exosome crosstalk is extremely complex and it is only beginning to be recognized and documented. This review is focused on discussing the roles of autophagy and exosomes in the cancer cell's adaptation to the tumor microenvironment and how the two pathways are coordinately regulated to facilitate cancer cell survival.

Keywords: Autophagy; Chemoresistance; Exosomes; Metastasis; Tumor microenvironment

DOI: https://doi.org/10.1016/j.lfs.2022.120552