bims-unfpre 2021-05-16 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2021‒05‒16
twelve papers selected by
Susan Logue
University of Manitoba

Pathological β-Cell Endoplasmic Reticulum Stress in Type 2 Diabetes: Current Evidence.
Interferon signaling suppresses the unfolded protein response and induces cell death in hepatocytes accumulating hepatitis B surface antigen.
Bifidobacterium dentium-derived y-glutamylcysteine suppresses ER-mediated goblet cell stress and reduces TNBS-driven colonic inflammation.
Molecular Modulation by Lentivirus-Delivered Specific shRNAs in Endoplasmic Reticulum Stressed Neurons.
Vitamin D3 suppresses intestinal epithelial stemness via ER stress induction in intestinal organoids.
Endoplasmic reticulum stress regulates the intestinal stem cell state through CtBP2.
Diabetic nephropathy in mice is aggravated by the absence of podocyte IRE1 and is correlated with reduced kidney ADH1 expression.
Integrated Structural Analysis of N-Glycans and Free Oligosaccharides Allows for a Quantitative Evaluation of ER Stress.
Allopurinol ameliorates high fructose diet induced hepatic steatosis in diabetic rats through modulation of lipid metabolism, inflammation, and ER stress pathway.
Unfolded protein response in the activation-induced biological processes of CD8+ T cells.
Vps34 and TOR Kinases Coordinate HAC1 mRNA Translation in the presence or absence of Ire1-dependent Splicing.
Persulfidation of ATG18a regulates autophagy under ER stress in Arabidopsis.

Front Endocrinol (Lausanne). 2021 ;12 650158

Pathological β-Cell Endoplasmic Reticulum Stress in Type 2 Diabetes: Current Evidence.

Neha Shrestha, Elisa De Franco, Peter Arvan, Miriam Cnop.

  The notion that in diabetes pancreatic β-cells express endoplasmic reticulum (ER) stress markers indicative of increased unfolded protein response (UPR) signaling is no longer in doubt. However, what remains controversial is whether this increase in ER stress response actually contributes importantly to the β-cell failure of type 2 diabetes (akin to 'terminal UPR'), or whether it represents a coping mechanism that represents the best attempt of β-cells to adapt to changes in metabolic demands as presented by disease progression. Here an intercontinental group of experts review evidence for the role of ER stress in monogenic and type 2 diabetes in an attempt to reconcile these disparate views. Current evidence implies that pancreatic β-cells require a regulated UPR for their development, function and survival, as well as to maintain cellular homeostasis in response to protein misfolding stress. Prolonged ER stress signaling, however, can be detrimental to β-cells, highlighting the importance of "optimal" UPR for ER homeostasis, β-cell function and survival.

Keywords:  ATF6 (activating transcription factor 6); IRE1 (inositol-requiring enzyme 1); PERK (PKR-like endoplasmic reticulum kinase); endoplasmic reticulum; insulin; stress; unfolded protein response

DOI:  https://doi.org/10.3389/fendo.2021.650158
PLoS Pathog. 2021 May 12. 17(5): e1009228

Interferon signaling suppresses the unfolded protein response and induces cell death in hepatocytes accumulating hepatitis B surface antigen.

Ian Baudi, Masanori Isogawa, Federica Moalli, Masaya Onishi, Keigo Kawashima, Yuji Ishida, Chise Tateno, Yusuke Sato, Hideyoshi Harashima, Hiroyasu Ito, Tetsuya Ishikawa, Takaji Wakita, Matteo Iannacone, Yasuhito Tanaka.

Virus infection, such as hepatitis B virus (HBV), occasionally causes endoplasmic reticulum (ER) stress. The unfolded protein response (UPR) is counteractive machinery to ER stress, and the failure of UPR to cope with ER stress results in cell death. Mechanisms that regulate the balance between ER stress and UPR are poorly understood. Type 1 and type 2 interferons have been implicated in hepatic flares during chronic HBV infection. Here, we examined the interplay between ER stress, UPR, and IFNs using transgenic mice that express hepatitis B surface antigen (HBsAg) (HBs-Tg mice) and humanized-liver chimeric mice infected with HBV. IFNα causes severe and moderate liver injury in HBs-Tg mice and HBV infected chimeric mice, respectively. The degree of liver injury is directly correlated with HBsAg levels in the liver, and reduction of HBsAg in the transgenic mice alleviates IFNα mediated liver injury. Analyses of total gene expression and UPR biomarkers' protein expression in the liver revealed that UPR is induced in HBs-Tg mice and HBV infected chimeric mice, indicating that HBsAg accumulation causes ER stress. Notably, IFNα administration transiently suppressed UPR biomarkers before liver injury without affecting intrahepatic HBsAg levels. Furthermore, UPR upregulation by glucose-regulated protein 78 (GRP78) suppression or low dose tunicamycin alleviated IFNα mediated liver injury. These results suggest that IFNα induces ER stress-associated cell death by reducing UPR. IFNγ uses the same mechanism to exert cytotoxicity to HBsAg accumulating hepatocytes. Collectively, our data reveal a previously unknown mechanism of IFN-mediated cell death. This study also identifies UPR as a potential target for regulating ER stress-associated cell death.

DOI: https://doi.org/10.1371/journal.ppat.1009228
Gut Microbes. 2021 Jan-Dec;13(1):13(1): 1-21

Bifidobacterium dentium-derived y-glutamylcysteine suppresses ER-mediated goblet cell stress and reduces TNBS-driven colonic inflammation.

Melinda A Engevik, Beatrice Herrmann, Wenly Ruan, Amy C Engevik, Kristen A Engevik, Faith Ihekweazu, Zhongcheng Shi, Berkley Luck, Alexandra L Chang-Graham, Magdalena Esparza, Susan Venable, Thomas D Horvath, Sigmund J Haidacher, Kathleen M Hoch, Anthony M Haag, Deborah A Schady, Joseph M Hyser, Jennifer K Spinler, James Versalovic.

  Endoplasmic reticulum (ER) stress compromises the secretion of MUC2 from goblet cells and has been linked with inflammatory bowel disease (IBD). Although Bifidobacterium can beneficially modulate mucin production, little work has been done investigating the effects of Bifidobacterium on goblet cell ER stress. We hypothesized that secreted factors from Bifidobacterium dentium downregulate ER stress genes and modulates the unfolded protein response (UPR) to promote MUC2 secretion. We identified by mass spectrometry that B. dentium secretes the antioxidant γ-glutamylcysteine, which we speculate dampens ER stress-mediated ROS and minimizes ER stress phenotypes. B. dentium cell-free supernatant and γ-glutamylcysteine were taken up by human colonic T84 cells, increased glutathione levels, and reduced ROS generated by the ER-stressors thapsigargin and tunicamycin. Moreover, B. dentium supernatant and γ-glutamylcysteine were able to suppress NF-kB activation and IL-8 secretion. We found that B. dentium supernatant, γ-glutamylcysteine, and the positive control IL-10 attenuated the induction of UPR genes GRP78, CHOP, and sXBP1. To examine ER stress in vivo, we first examined mono-association of B. dentium in germ-free mice which increased MUC2 and IL-10 levels compared to germ-free controls. However, no changes were observed in ER stress-related genes, indicating that B. dentium can promote mucus secretion without inducing ER stress. In a TNBS-mediated ER stress model, we observed increased levels of UPR genes and pro-inflammatory cytokines in TNBS treated mice, which were reduced with addition of live B. dentium or γ-glutamylcysteine. We also observed increased colonic and serum levels of IL-10 in B. dentium- and γ-glutamylcysteine-treated mice compared to vehicle control. Immunostaining revealed retention of goblet cells and mucus secretion in both B. dentium- and γ-glutamylcysteine-treated animals. Collectively, these data demonstrate positive modulation of the UPR and MUC2 production by B. dentium-secreted compounds.

Keywords:  ER-stress; IBD; IL-10; MUC2; bifidobacteria; colitis; goblet cells; organoids

DOI:  https://doi.org/10.1080/19490976.2021.1902717
J Vis Exp. 2021 Apr 24.

Molecular Modulation by Lentivirus-Delivered Specific shRNAs in Endoplasmic Reticulum Stressed Neurons.

Carolina Morales, Mariano Bisbal, Mariana Bollo.

The accumulation of unfolded proteins within the endoplasmic reticulum (ER), caused by any stress condition, triggers the unfolded protein response (UPR) through the activation of specialized sensors. UPR attempts first to restore homeostasis; but if damage persists the signaling induces apoptosis. There is increasing evidence that sustained and unresolved ER stress contributes to many pathological conditions including neurodegenerative diseases. Because the UPR controls cell fate by switching between cytoprotective and apoptotic processes, it is essential to understand the events defining this transition, as well as the elements involved in its modulation. Recently, we demonstrated that abnormal GM2 ganglioside accumulation causes depletion of ER Ca2+ content, which in turn activates PERK (PKR-like-ER kinase), one of the UPR sensors. Furthermore, PERK signaling participates in the neurite atrophy and apoptosis induced by GM2 accumulation. In this respect, we have established an experimental system that allows us to molecularly modulate the expression of downstream PERK components and thus change vulnerability of neurons to undergo neuritic atrophy. We performed knockdown of calcineurin (cytoprotective) and CHOP (pro-apoptotic) expression in rat cortical neuronal cultures. Cells were infected with lentivirus-delivered specific shRNA and then treated with GM2 at different times, fixed and immunostained with anti-MAP2 (microtube-associated protein 2) antibody. Later, cell images were recorded using a fluorescence microscope and total neurite outgrowth was evaluated by using the public domain image processing software ImageJ. The inhibition of expression of those PERK signaling components clearly made it possible to either accelerate or delay the neuritic atrophy induced by ER stress. This approach might be used in cell system models of ER stress to evaluate the vulnerability of neurons to neurite atrophy.

DOI: https://doi.org/10.3791/61974
Stem Cell Res Ther. 2021 May 13. 12(1): 285

Vitamin D3 suppresses intestinal epithelial stemness via ER stress induction in intestinal organoids.

Panida Sittipo, Hyun Kyu Kim, Jaeseok Han, Man Ryul Lee, Yun Kyung Lee.

  BACKGROUND: Vitamin D3 is important for normal function of the intestinal epithelial cells (IECs). In this study, we aimed to investigate the effects of vitamin D3 on the differentiation, stemness, and viability of healthy IECs in intestinal organoids.METHODS: Intestinal organoids derived from mouse small intestine were treated with vitamin D3, and the effects on intestinal stemness and differentiation were evaluated using real-time PCR and immunofluorescence staining of the distinct lineage markers. Cell viability was analyzed using viability and apoptosis assays.
RESULTS: Vitamin D3 enhanced IEC differentiation into the distinct lineages of specialized IECs, including Paneth, goblet, and enteroendocrine cells and absorptive enterocytes. Decreased expression levels of leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) and the presence of several LGR5-green fluorescent protein (GFP)-positive cells were observed in vitamin D3-treated organoids derived from LGR5-GFP mice. The formation of the crypt-villus structure was also inhibited by vitamin D3, suggesting that vitamin D3 suppresses intestinal cell stemness. Furthermore, the expression levels of unfolded protein response genes, C/EBP homologous protein (CHOP), and activating transcription factor 6 (ATF6) were upregulated in vitamin D3-treated organoids. Moreover, vitamin D3 promoted apoptotic cell death in intestinal cells, which may be associated with the decrease in intestinal stemness. LGR5 gene expression, ISC number, and apoptotic cell death were partially recovered in the presence of the ER stress inhibitor tauroursodeoxycholic acid (TUDCA), suggesting that intestinal stemness suppression and intestinal apoptosis occurred via ER stress activation.
CONCLUSIONS: Our study provides important insights into the effects of vitamin D3 on the induction of IEC differentiation and apoptotic cell death, and inhibition of intestinal stemness accompanied by ER stress augmentation.

Keywords:  Endoplasmic reticulum (ER) stress; Intestinal epithelial cells (IECs); Intestinal organoids; Vitamin D3

DOI:  https://doi.org/10.1186/s13287-021-02361-2
Sci Rep. 2021 May 10. 11(1): 9892

Endoplasmic reticulum stress regulates the intestinal stem cell state through CtBP2.

Bartolomeus J Meijer, Wouter L Smit, Pim J Koelink, Barbara F Westendorp, Ruben J de Boer, Jonathan H M van der Meer, Jacqueline L M Vermeulen, James C Paton, Adrienne W Paton, Jun Qin, Evelien Dekker, Vanesa Muncan, Gijs R van den Brink, Jarom Heijmans.

Enforcing differentiation of cancer stem cells is considered as a potential strategy to sensitize colorectal cancer cells to irradiation and chemotherapy. Activation of the unfolded protein response, due to endoplasmic reticulum (ER) stress, causes rapid stem cell differentiation in normal intestinal and colon cancer cells. We previously found that stem cell differentiation was mediated by a Protein kinase R-like ER kinase (PERK) dependent arrest of mRNA translation, resulting in rapid protein depletion of WNT-dependent transcription factor c-MYC. We hypothesize that ER stress dependent stem cell differentiation may rely on the depletion of additional transcriptional regulators with a short protein half-life that are rapidly depleted due to a PERK-dependent translational pause. Using a novel screening method, we identify novel transcription factors that regulate the intestinal stem cell fate upon ER stress. ER stress was induced in LS174T cells with thapsigargin or subtilase cytotoxin (SubAB) and immediate alterations in nuclear transcription factor activity were assessed by the CatTFRE assay in which transcription factors present in nuclear lysate are bound to plasmid DNA, co-extracted and quantified using mass-spectrometry. The role of altered activity of transcription factor CtBP2 was further examined by modification of its expression levels using CAG-rtTA3-CtBP2 overexpression in small intestinal organoids, shCtBP2 knockdown in LS174T cells, and familial adenomatous polyposis patient-derived organoids. CtBP2 overexpression organoids were challenged by ER stress and ionizing irradiation. We identified a unique set of transcription factors with altered activation upon ER stress. Gene ontology analysis showed that transcription factors with diminished binding were involved in cellular differentiation processes. ER stress decreased CtBP2 protein expression in mouse small intestine. ER stress induced loss of CtBP2 expression which was rescued by inhibition of PERK signaling. CtBP2 was overexpressed in mouse and human colorectal adenomas. Inducible CtBP2 overexpression in organoids conferred higher clonogenic potential, resilience to irradiation-induced damage and a partial rescue of ER stress-induced loss of stemness. Using an unbiased proteomics approach, we identified a unique set of transcription factors for which DNA-binding activity is lost directly upon ER stress. We continued investigating the function of co-regulator CtBP2, and show that CtBP2 mediates ER stress-induced loss of stemness which supports the intestinal stem cell state in homeostatic stem cells and colorectal cancer cells.

DOI: https://doi.org/10.1038/s41598-021-89326-w
Ann Transl Med. 2021 Apr;9(8): 636

Diabetic nephropathy in mice is aggravated by the absence of podocyte IRE1 and is correlated with reduced kidney ADH1 expression.

Liping Xie, Kaifeng Guo, Sijia Lu, Ning Wang, Yanping Wang, Haibing Chen, Junli Liu, Weiping Jia.

  Background: Inositol-requiring enzyme 1 (IRE1) plays a critical role in attenuating endoplasmic reticulum (ER) stress associated with renal injury which may also be a factor in diabetic nephropathy (DN). Alcohol dehydrogenase type I (ADH1) activity is prominent in the kidney, ADH1 activity is also reported to exert protective effects against ER stress that are not caused by alcohol consumption. However, the role of IRE1 in DN and the correlation between IRE1 and ADH1 activity remain unclear.Methods: IRE1α floxed mice (Ire1f/f ) of C57BL/6J background were established and crossbred with Ire1αf/f mice to produce podocyte-specific IRE1α knockout mice. Male db/db mice (C57BLKS/J-leprdb/leprdb mice) were used as a DN model. Male mice were made diabetic by injection of streptozotocin. pLKO.1-based vectors encoding short hairpin RNA (shRNA) specific to the IRE1α gene were transfected into HEK293T cells to knockdown IRE1α in mouse podocytes. ELISA, Masson's staining, and electron microscopy were performed to analyze the development of DN. The ADH1 expression was assayed by qPCR and western blot.
Results: We found that IRE activity was increased in the glomeruli of DN mouse models. In contrast, ADH1 expression was decreased in these models and mice with podocyte-specific disruption of IRE1 (PKO mice). PKO mice that were made diabetic using strepto-zotocin exhibited accelerated proteinuria, enhanced glomerular fibrosis, and podocyte cell death. In addition, in cultured podocytes, the knockdown of IRE1 downregulated the ADH1 mRNA expression and induced ER stress, consistent with the result of PKO mice, while its detrimental effects were reversed by ADH1 overexpression.
Conclusions: Activation of IRE1 in podocytes serves to limit the progress of DN. The dependence of kidney ADH1 expression on podocyte IRE1 further suggests that ADH1 activity may play an important role downstream of IRE1 in protecting against DN.

Keywords:  Inositol-requiring enzyme 1 (IRE1); albuminuria; alcohol dehydrogenase type I (ADH1); diabetic nephropathy (DN); podocyte

DOI:  https://doi.org/10.21037/atm-20-6356
Biochemistry. 2021 May 13.

Integrated Structural Analysis of N-Glycans and Free Oligosaccharides Allows for a Quantitative Evaluation of ER Stress.

Naoki Fujitani, Shigeru Ariki, Yoshihiro Hasegawa, Yasuaki Uehara, Atsushi Saito, Motoko Takahashi.

Endoplasmic reticulum (ER) stress has been reported in a variety of diseases. Although ER stress can be detected using specific markers, it is still difficult to quantitatively evaluate the degree of stress and to identify the cause of the stress. The ER is the primary site for folding of secretory or transmembrane proteins as well as the site where glycosylation is initiated. This study therefore postulates that tracing the biosynthetic pathway of asparagine-linked glycans (N-glycans) would be a reporter for reflecting the state of the ER and serve as a quantitative descriptor of ER stress. Glycoblotting-assisted mass spectrometric analysis of the HeLa cell line enabled quantitative determination of the changes in the structures of N-glycans and degraded free oligosaccharides (fOSs) in response to tunicamycin- or thapsigargin-induced ER stress. The integrated analysis of neutral and sialylated N-glycans and fOSs showed the potential to elucidate the cause of ER stress, which cannot be readily done by protein markers alone. Changes in the total amount of glycans, increase in the ratio of high-mannose type N-glycans, increase in fOSs, and changes in the ratio of sialylated N-glycans in response to ER stress were shown to be potential descriptors of ER stress. Additionally, drastic clearance of accumulated N-glycans was observed in thapsigargin-treated cells, which may suggest the observation of ER stress-mediated autophagy or ER-phagy in terms of glycomics. Quantitative analysis of N-glycoforms composed of N-glycans and fOSs provides the dynamic indicators reflecting the ER status and the promising strategies for quantitative evaluation of ER stress.

DOI: https://doi.org/10.1021/acs.biochem.0c00969
Sci Rep. 2021 May 10. 11(1): 9894

Allopurinol ameliorates high fructose diet induced hepatic steatosis in diabetic rats through modulation of lipid metabolism, inflammation, and ER stress pathway.

In-Jin Cho, Da-Hee Oh, Jin Yoo, You-Cheol Hwang, Kyu Jeung Ahn, Ho-Yeon Chung, Soung Won Jeong, Ju-Young Moon, Sang-Ho Lee, Sung-Jig Lim, In-Kyung Jeong.

Excess fructose consumption contributes to development obesity, metabolic syndrome, and nonalcoholic fatty liver disease (NAFLD). Uric acid (UA), a metabolite of fructose metabolism, may have a direct role in development of NAFLD, with unclear mechanism. This study aimed to evaluate role of fructose and UA in NAFLD and explore mechanisms of allopurinol (Allo, a UA lowering medication) on NAFLD in Otsuka Long-Evans Tokushima Fatty (OLETF) rats fed a high fructose diet (HFrD), with Long-Evans Tokushima Otsuka (LETO) rats used as a control. There were six groups: LETO, LETO-Allo, OLETF, OLETF-Allo, OLETF-HFrD, and OLETF-HFrD-Allo. HFrD significantly increased body weight, epididymal fat weight, and serum concentrations of UA, cholesterol, triglyceride, HbA1c, hepatic enzymes, HOMA-IR, fasting insulin, and two hour-glucose after intraperitoneal glucose tolerance tests, as well as NAFLD activity score of liver, compared to the OLETF group. Allopurinol treatment significantly reduced hepatic steatosis, epididymal fat, serum UA, HOMA-IR, hepatic enzyme levels, and cholesterol in the OLETF-HFrD-Allo group. Additionally, allopurinol significantly downregulated expression of lipogenic genes, upregulated lipid oxidation genes, downregulated hepatic pro-inflammatory cytokine genes, and decreased ER-stress induced protein expression, in comparison with the OLETF-HFrD group. In conclusion, allopurinol ameliorates HFrD-induced hepatic steatosis through modulation of hepatic lipid metabolism, inflammation, and ER stress pathway. UA may have a direct role in development of fructose-induced hepatic steatosis, and allopurinol could be a candidate for prevention or treatment of NAFLD.

DOI: https://doi.org/10.1038/s41598-021-88872-7
Pharmacol Res. 2021 May 06. pii: S1043-6618(21)00238-3. [Epub ahead of print]169 105654

Unfolded protein response in the activation-induced biological processes of CD8+ T cells.

Yingying Shi, Yichao Lu, Jian You.

  As the central part of cellular immunity, primed CD8+ T cells go through different phases of response including activation, clonal expansion, contraction and steady-state turnover, which is accompanied by a fluctuating level of endoplasmic reticulum stress that leads to the elicitation of unfolded protein response (UPR). In turn, UPR casts profound impacts on the activation-induced biological processes of CD8+ T cells, which may greatly determine the magnitude and quality of T-cell based immunity. However, current understanding of the interconnectivity between UPR and T cell-biology is not comprehensive, with details of manipulation largely unexplored. In this review, the molecular basis of UPR involved in different stages of activated CD8+ T cells and its immunological significance are discussed, with potential strategies of regulation proposed, which may provide instructive guidance for the design and optimization of T cell-based immunotherapy.

Keywords:  Activation-induced biological processes; CD8(+) T cells; Immunotherapy; Regulation strategy; UPR

DOI:  https://doi.org/10.1016/j.phrs.2021.105654
Mol Cell Biol. 2021 May 10. pii: MCB.00662-20. [Epub ahead of print]

Vps34 and TOR Kinases Coordinate HAC1 mRNA Translation in the presence or absence of Ire1-dependent Splicing.

Jagadeesh Kumar Uppala, Sankhajit Bhattacharjee, Madhusudan Dey.

In the budding yeast Saccharomyces cerevisiae an mRNA, called HAC1, exists in a translationally repressed form in the cytoplasm. Under conditions of cellular stress, such as when unfolded proteins accumulate inside the endoplasmic reticulum (ER), an RNase Ire1 removes an intervening sequence (intron) from the HAC1 mRNA by non-conventional cytosolic splicing. Removal of the intron results in translational de-repression of HAC1 mRNA and production of a transcription factor that activates expressions of many enzymes and chaperones to increase the protein-folding capacity of the cell. Here, we show that Ire1-mediated RNA cleavage requires Watson-Crick base pairs in two RNA hairpins, which are located at the HAC1 mRNA exon-intron junctions. Then, we show that the translational de-repression of HAC1 mRNA can occur independent of cytosolic splicing. These results are obtained from HAC1 variants that translated an active Hac1 protein from the un-spliced mRNA. Additionally, we show that the phosphatidylinositol-3-kinase Vps34 and the nutrient-sensing kinases TOR and GCN2 are key regulators of HAC1 mRNA translation and consequently the ER stress responses. Collectively, our data suggest that the cytosolic splicing and the translational de-repression of HAC1 mRNA are coordinated by unique and parallel networks of signaling pathways.

DOI: https://doi.org/10.1128/MCB.00662-20
Proc Natl Acad Sci U S A. 2021 May 18. pii: e2023604118. [Epub ahead of print]118(20):

Persulfidation of ATG18a regulates autophagy under ER stress in Arabidopsis.

Angeles Aroca, Inmaculada Yruela, Cecilia Gotor, Diane C Bassham.

  Hydrogen sulfide (H2S) is an endogenously generated gaseous signaling molecule, which recently has been implicated in autophagy regulation in both plants and mammals through persulfidation of specific targets. Persulfidation has been suggested as the molecular mechanism through which sulfide regulates autophagy in plant cells. ATG18a is a core autophagy component that is required for bulk autophagy and also for reticulophagy during endoplasmic reticulum (ER) stress. In this research, we revealed the role of sulfide in plant ER stress responses as a negative regulator of autophagy. We demonstrate that sulfide regulates ATG18a phospholipid-binding activity by reversible persulfidation at Cys103, and that this modification activates ATG18a binding capacity to specific phospholipids in a reversible manner. Our findings strongly suggest that persulfidation of ATG18a at C103 regulates autophagy under ER stress, and that the impairment of persulfidation affects both the number and size of autophagosomes.

Keywords:  ATG18a; ER stress; autophagy; hydrogen sulfide; persulfidation

DOI:  https://doi.org/10.1073/pnas.2023604118