bims-unfpre 2023-01-29 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2023–01–29
thirteen papers selected by
Susan Logue, University of Manitoba

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.
Infancy-onset diabetes caused by de-regulated AMPylation of the human endoplasmic reticulum chaperone BiP.
A novel fluorescent endoplasmic reticulum marker for super-resolution imaging in live cells.
A glaucoma-associated OPTN polymorphism, M98K sensitizes retinal cells to endoplasmic reticulum stress and tumor necrosis factor α.
ADP-ribose transferase PARP16 mediated-unfolded protein response contributes to neuronal cell damage in cerebral ischemia/reperfusion.
The role of endoplasmic reticulum stress in endometriosis.
Genomic and clinical features of endoplasmic reticulum stress factor in digestive system pan-cancer studies.
Impairment of RPN4, a transcription factor, induces ER stress and lipid abnormality in Saccharomyces cerevisiae.
Evaluating the effect of basic fibroblast growth factor on the progression of NASH disease by inhibiting ceramide synthesis and ER stress-related pathways.
Endoplasmic reticulum stress related IncRNA signature predicts the prognosis and immune response evaluation of uterine corpus endometrial carcinoma.
Sex differences in islet stress responses support female β cell resilience.
Endoplasmic reticulum associated degradation is essential for maintaining the viability or function of mature myelinating cells in adults.
Ufmylation reconciles salt stress-induced unfolded protein responses via ER-phagy in Arabidopsis.

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
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
FEBS Lett. 2023 Jan 24.

A novel fluorescent endoplasmic reticulum marker for super-resolution imaging in live cells.

Kai Han, Shuhan Huang, Jie Kong, Yang Yang, Lei Shi, Yali Ci.

  Endoplasmic reticulum (ER) is a highly complicated and dynamic organelle that actively changes its shape and communicates with other organelles. Visualization of ER in live cells is of great importance to understand cellular activities. Here, we designed a novel ER marker, RR-mNeonGreen, which comprised an N-terminal ER retention signal, a bright fluorescent protein (mNeonGreen) and a C-terminal transmembrane region. Colocalization of RR-mNeonGreen with mCherry-KDEL verified that RR-mNeonGreen perfectly labeled the ER. RR-mNeonGreen showed better continuity of ER tubules when imaged by super-resolution microscopy. Moreover, RR-mNeonGreen is competent for live-cell imaging of ER dynamics and tracing of the interaction between ER and mitochondria at high spatiotemporal resolution. In summary, RR-mNeonGreen is a novel ER marker for super-resolution live-cell imaging with multiple merits.

Keywords:  ER marker; RR-mNeonGreen; dynamics; live-cell imaging; super-resolution

DOI:  https://doi.org/10.1002/1873-3468.14581
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
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
Cell Stress Chaperones. 2023 Jan 25.

The role of endoplasmic reticulum stress in endometriosis.

Hussein Riyadh Abdul Kareem Al-Hetty, Ahmed Darweesh Jabbar, Vladimir F Eremin, Abeer Mohsen Jabbar, Abduladheem Turki Jalil, Ali G Al-Dulimi, Hasanain A J Gharban, Muhammad Usman Faryad Khan, Marwan Mahmood Saleh.

  Endometriosis is a chronic gynecologic disorder characterized by abnormal growth of endometrium-like tissues in the ectopic regions of the pelvic peritoneum. The pathophysiology of endometriosis is not completely understood; however, excessive endometrial cell proliferation together with resistance to apoptosis facilitates the migration, implantation, and survival of endometrial cells in the distant sites. Endoplasmic reticulum (ER) stress response (also called unfolded protein response) is a cellular defense mechanism triggered by ER stress. When severe enough, the so-called response initiates cell suicide, i.e., apoptosis. Therefore, therapeutic induction of ER stress in endometriotic cells could promote apoptosis and contribute to the management of disease. In this review, we discuss the pathogenic role of ER stress in endometriosis and the most recent findings regarding the induction of ER stress in connection with endometriosis.

Keywords:  Endometriosis; Endoplasmic reticulum stress; Unfolded protein responses

DOI:  https://doi.org/10.1007/s12192-023-01323-2
Front Oncol. 2022 ;12 1072576

Genomic and clinical features of endoplasmic reticulum stress factor in digestive system pan-cancer studies.

Sheng Yao, Yuanquan Yu, Liyi Xu, Xiang Pan.

   Introduction: Digestive system pan-cancer is one of the lethal malignant tumors, which have the propensity for poor prognosis and difficult treatment. Endoplasmic reticulum (ER) stress has served as a pivotal role in the progression of the tumor, while the implication of ER stress on digestive system pan-cancers still needs elucidation, especially from the perspective of clinical outcome and that of genomic features.
Methods: First, Among the ER STRESS factors from the REACTOME_UNFOLDED_PROTEIN_RESPONSE_UPR (113 genes) and HALLMARK_UNFOLDED_PROTEIN_RESPONSE (92 genes) terms, 153 ER STRESS regulators were identified after removing replicates. The somatic mutation data and copy number variation data of gastrointestinal pan-cancer were downloaded from The Cancer Genome Atlas (TCGA) database. Then, we explored the clinical outcome and genetic mutation of ER stress-related differentially expressed genes (DEGs) by multiple bioinformatics analysis. Subsequently, we analyzed the Spearman correlation between the drug sensitivity of 179 gastrointestinal anticancer drugs and the transcriptional expression of 153 ER stress factors in 769 cancer cell lines of the GDSC2 cohort. Next, ssGSEA method was used to quantify the immune cell infiltration scores in the tumor microenvironment, and Spearman correlation was used to calculate the correlation between ER stress scores and immune cell infiltration. Finally, we analyzed the cellular origin of ER stress factor dysregulation.
Results: We analyzed the genomic changes and clinical outcomes of ER stress factors in different tumors of gastrointestinal pan-cancer. Endoplasmic reticulum stress factor (ER) in digestive tract tumors showed high SNV mutation frequency, less methylation dysregulation and was associated with multiple oncogenic pathways. Endoplasmic reticulum stress factor (ER) is a risk factor for many cancers, but the effect on overall survival in rectal adenocarcinoma is opposite to that in other gastrointestinal tumors. And ER stress factors are highly correlated with drugs that target important pathways.
Discussion: Based on the clinical prognosis and genomic analysis of ER stress-related factors in patients with gastrointestinal pan-cancer, this study provides a new direction for further research on gastrointestinal pan-cancer.

Keywords:  clinical feature; digestive system pan-cancer; endoplasmic reticulum stress; genomic feature; prognosis; tumor microenvironment

DOI:  https://doi.org/10.3389/fonc.2022.1072576
Mol Cell Biochem. 2023 Jan 27.

Impairment of RPN4, a transcription factor, induces ER stress and lipid abnormality in Saccharomyces cerevisiae.

Bhanupriya Nagaraj, Antonisamy William James, Arul Mathivanan, Vasanthi Nachiappan.

  Accumulation of misfolded/unfolded proteins in the endoplasmic reticulum (ER) induces ER stress. The transcription factor RPN4 {"Regulatory Particle Non-ATPase"} regulates protein homeostasis by degrading proteins that elude proper folding or assembly via the proteasomal degradation pathway. Here, we studied the lipid alterations exerted by Saccharomyces cerevisiae to mitigate (ER) stress during adaptive responses in rpn4∆ cells. The loss of RPN4-induced ER stress increased phospholipid synthesis, leading to altered membrane structures and accumulation of neutral lipids, causing an increase in lipid droplets (LDs). There was a significant upregulation of genes involved in neutral lipid and membrane lipid synthesis in rpn4∆ cells. Overexpression of RPN4 restored the defects caused by rpn4∆ cells. Thus, our study provides new insight that RPN4 impacts lipid homeostasis.

Keywords:  ER stress; Neutral lipids; Phospholipids; RPN4; Saccharomyces cerevisiae

DOI:  https://doi.org/10.1007/s11010-022-04623-w
Eur J Pharmacol. 2023 Jan 21. pii: S0014-2999(23)00047-X. [Epub ahead of print]942 175536

Evaluating the effect of basic fibroblast growth factor on the progression of NASH disease by inhibiting ceramide synthesis and ER stress-related pathways.

Shahrzad Rahimi, Seyyed Abdolhamid Angaji, Ahmad Majd, Behzad Hatami, Kaveh Baghaei.

  Non-alcoholic steatohepatitis (NASH) is associated with intrahepatic lipid accumulation, inflammation, and hepatocyte death. Several studies have indicated that high-fat diets increase ceramide synthases-6 (CerS-6) expression and a concomitant elevation of C16-ceramides, which can modulate endoplasmic reticulum (ER) stress and further contribute to the progression of NASH. Ceramide levels have reportedly been impacted by basic fibroblast growth factor (bFGF) in various diseases. This study looked into the role of bFGF on CerS6/C16-ceramide and ER stress-related pathways in a mouse model of NASH. Male C57BL/6J mice were fed a western diet (WD) combined with carbon tetrachloride (CCl4) for eight weeks. Next, bFGF was injected into the NASH mice for seven days of continuous treatment. The effects of bFGF on NASH endpoints (including steatosis, inflammation, ballooning, and fibrosis), ceramide levels and ER-stress-induced inflammation, reactive oxygen species (ROS) production, and apoptosis were evaluated. Treatment with bFGF significantly reduced CerS-6/C16-ceramide. Further, the inflammatory condition was alleviated with reduction of nuclear factor-kappa B (NF-κB), tumor necrosis factor-alpha (TNF-α), and interleukin 6 (IL-6) gene expression. ROS level was also reduced. ER stress-related cell death diminished by reducing C/EBP homologous protein (CHOP) mRNA expression and caspase 3 activity. Furthermore, activation of the hepatic stellate cells was inhibited in the bFGF-treated mice by lowering the amount of alpha-smooth muscle actin (α-SMA) at the mRNA and protein level. According to our findings, CerS-6/C16-ceramide alteration impacts ER stress-mediated inflammation, oxidative stress, and apoptosis. The bFGF treatment effectively attenuated the development of NASH by downregulating CerS-6/C16-ceramide and subsequent ER stress-related pathways.

Keywords:  Basic fibroblast growth factor; Ceramide; Endoplasmic reticulum stress; Inflammation; Nonalcoholic steatohepatitis; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.ejphar.2023.175536
Front Oncol. 2022 ;12 1064223

Endoplasmic reticulum stress related IncRNA signature predicts the prognosis and immune response evaluation of uterine corpus endometrial carcinoma.

Jun Chen, Licong Shen, Yongwen Yang.

   Background: Endoplasmic reticulum (ER) stress is closely related to the occurrence, development and treatment of tumors. Recent studies suggest ER stress as a therapeutic strategy of choice for cancer. However, ER stress-related long non-coding RNA (lncRNA) predictive value in endometrial carcinoma (UCEC) remains to be further evaluated. The purpose of this study was to establish relies on the signature of ER stress-related lncRNA forecast to predict the prognosis of patients with UCEC.
Methods: We downloaded the RNA expression profile dataset and matched clinical data from the Cancer Genome Atlas (TCGA) database, and applied univariate and multivariate Cox regression analysis to build predictive signature. Kaplan-meier method was used to evaluate overall survival (OS) and disease-free survival (DFS). Gene set enrichment analysis (GSEA) was used to study the functional characteristics. Single sample Gene set enrichment analysis (ssGSEA) was used to analyze the relationship between immune status and predicted signature. Correlations between the potential usefulness of treatment for UCEC patients and predictive signature were also analyzed.
Results: We established a signature composed of eight ER stress-related lncRNAs (MIR34AHG, AC073842.2, PINK1AS, AC024909.2, MIR31HG, AC007422.2, AC061992.1, AC003102.1). The signature of ER stress-related lncRNA provided better diagnostic value compared with age and tumor grade, and the area under the receiver operating curve was 0.788. The overall and disease-free survival probability of patients in the high-risk group is lower than that in the low-risk group. GSEA indicated that the pathways were mainly enriched for cancer, immunity and reproduction related pathways. ss-GSEA shows that prediction signature and activation of dendritic cells, immature dendritic cells, T helper cells and immune status of the Treg are significantly related. High-risk groups may against PD - 1/L1 immunotherapy and JNK inhibitors VIII, Z.LLNle.CHO, DMOG and JNK. 9 l more sensitive.
Conclusion: The ER stress signature can independently predict the prognosis of UCEC patients, and provide guidance for conventional chemotherapy and immunotherapy of UCEC patients.

Keywords:  ER stress; drug therapy; immune infiltration; lncRNAs; uterine corpus endometrial carcinoma

DOI:  https://doi.org/10.3389/fonc.2022.1064223
Mol Metab. 2023 Jan 20. pii: S2212-8778(23)00012-1. [Epub ahead of print] 101678

Sex differences in islet stress responses support female β cell resilience.

George P Brownrigg, Yi Han Xia, Chieh Min Jamie Chu, Su Wang, Charlotte Chao, Jiashuo Aaron Zhang, Søs Skovsø, Evgeniy Panzhinskiy, Xiaoke Hu, James D Johnson, Elizabeth J Rideout.

   OBJECTIVE: Pancreatic β cells play a key role in maintaining glucose homeostasis; dysfunction of this critical cell type causes type 2 diabetes (T2D). Emerging evidence points to sex differences in β cells, but few studies have examined male-female differences in β cell stress responses and resilience across multiple contexts, including diabetes. Here, we address the need for high-quality information on sex differences in β cell and islet gene expression and function using both human and rodent samples.
METHODS: We compared β cell gene expression and insulin secretion in donors with T2D to non-diabetic donors in both males and females. In mice, we generated a well-powered islet RNAseq dataset from 20-week-old male and female siblings with similar insulin sensitivity. Our unbiased analysis of murine gene expression pointed to a sex difference in the endoplasmic reticulum (ER) stress response. Based on this analysis, we hypothesize female islets will be more resilient to ER stress than male islets. To test this, we subjected islets isolated from age-matched male and female mice to thapsigargin treatment and monitored protein synthesis, cell death, and β cell insulin production and secretion. Transcriptomic and proteomic analyses were used to characterize sex differences in islet responses to ER stress.
RESULTS: Our single-cell analysis of human β cells revealed sex-specific changes to gene expression and function in T2D, correlating with more robust insulin secretion in human islets isolated from female donors with T2D compared to male donors with T2D. In mice, RNA sequencing revealed differential enrichment of unfolded protein response pathway-associated genes, where female islets showed higher expression of genes linked with protein synthesis, folding, and processing. This differential expression was biologically significant, as islets isolated from female mice were more resilient to ER stress induction with thapsigargin. Specifically, female islets showed a greater ability to maintain glucose-stimulated insulin production and secretion during ER stress compared with males.
CONCLUSIONS: Our data demonstrate sex differences in β cell gene expression in both humans and mice, and that female β cells show a greater ability to maintain glucose-stimulated insulin secretion across multiple physiological and pathological contexts.

Keywords:  Diabetes mellitus; Endoplasmic reticulum stress; Pancreatic islets; Protein synthesis; Transcriptomics; β cells

DOI:  https://doi.org/10.1016/j.molmet.2023.101678
Glia. 2023 Jan 28.

Endoplasmic reticulum associated degradation is essential for maintaining the viability or function of mature myelinating cells in adults.

Shuangchan Wu, Wensheng Lin.

  Endoplasmic reticulum associated degradation (ERAD) is responsible for recognition and degradation of unfolded or misfolded proteins in the ER. Sel1L is essential for the ERAD activity of Sel1L-Hrd1 complex, the best-known ERAD machinery. Using a continuous Sel1L knockout mouse model (CNP/Cre; Sel1LloxP/loxP mice), our previous studies showed that Sel1L knockout in myelinating cells, oligodendrocytes in the central nervous system (CNS) and Schwann cells in the peripheral nervous system (PNS), leads to adult-onset myelin abnormalities in the CNS and PNS. Because Sel1L is deleted in myelinating cells of CNP/Cre; Sel1LloxP/loxP mice starting at very early stage of differentiation, it is impossible to rule out the possibility that the adult-onset myelin abnormalities in these mice results from developmental myelination defects caused by Sel1L knockout in myelinating cells during development. Thus, using an inducible Sel1L knockout mouse model (PLP/CreERT ; Sel1LloxP/loxP mice) that has normal, intact myelin and myelinating cells in the adult CNS and PNS prior to tamoxifen treatment, we sought to determine if Sel1L knockout in mature myelinating cells of adult mice leads to myelin abnormalities in the CNS and PNS. We showed that Sel1L knockout in mature myelinating cells caused ERAD impairment, ER stress and UPR activation. Interesting, Sel1L knockout in mature oligodendrocytes impaired their myelinating function by suppressing myelin protein translation, and resulted in progressive myelin thinning in the adult CNS. Conversely, Sel1L knockout in mature Schwann cells led to Schwann cell apoptosis and demyelination in the adult PNS. These findings demonstrate the essential roles of ERAD in mature myelinating cells in the adult CNS and PNS under physiological conditions.

Keywords:  ERAD; Schwann cell; Sel1L; UPR; myelin; oligodendrocyte

DOI:  https://doi.org/10.1002/glia.24346
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