bims-unfpre Biomed News
on Unfolded protein response
Issue of 2024–10–20
six papers selected by
Susan Logue, University of Manitoba
  1. A novel ER stress regulator ARL6IP5 induces reticulophagy to ameliorate the prion burden.
  2. IRE1α silences dsRNA to prevent taxane-induced pyroptosis in triple-negative breast cancer.
  3. ER stress aggravates NOD1-mediated inflammatory response leading to impaired nutrient metabolism in hepatoma cells.
  4. Targeting IRE1α reprograms the tumor microenvironment and enhances anti-tumor immunity in prostate cancer.
  5. Upadacitinib counteracts hepatic lipid deposition via the repression of JAK1/STAT3 signaling and AMPK/autophagy-mediated suppression of ER stress.
  6. The neurotrophic factor MANF regulates autophagy and lysosome function to promote proteostasis in Caenorhabditis elegans.
  1. Autophagy. 2024 Oct 12.
    A novel ER stress regulator ARL6IP5 induces reticulophagy to ameliorate the prion burden.
    Kajal Kamble, Ujjwal Kumar, Harsh Aahra, Mohit Yadav, Sumnil Bhola, Sarika Gupta.
      Prion disease is a fatal and infectious neurodegenerative disorder caused by the trans-conformation conversion of PRNP/PrPC to PRNP/PrPSc. Accumulated PRNP/PrPSc-induced ER stress causes chronic unfolded protein response (UPR) activation, which is one of the fundamental steps in prion disease progression. However, the role of various ER-resident proteins in prion-induced ER stress is elusive. This study demonstrated that ARL6IP5 is compensatory upregulated in response to chronically activated UPR in the cellular prion disease model (RML-ScN2a). Furthermore, overexpression of ARL6IP5 overcomes ER stress by lowering the expression of chronically activated UPR pathway proteins. We discovered that ARL6IP5 induces reticulophagy to reduce the PRNP/PrPSc burden by releasing ER stress. Conversely, the knockdown of ARL6IP5 leads to inefficient macroautophagic/autophagic flux and elevated PRNP/PrPSc burden. Our study also uncovered that ARL6IP5-induced reticulophagy depends on Ca2+-mediated AMPK activation and can induce 3 MA-inhibited autophagic flux. The detailed mechanistic study revealed that ARL6IP5-induced reticulophagy involves interaction with soluble reticulophagy receptor CALCOCO1 and lysosomal marker LAMP1, leading to degradation in lysosomes. Here, we delineate the role of ARL6IP5 as a novel ER stress regulator and reticulophagy inducer that can effectively reduce the misfolded PRNP/PrPSc burden. Our research opens up a new avenue of selective autophagy in prion disease and represents a potential therapeutic target.
    Keywords:  Autophagy; ER stress; Reticulophagy/er-phagy; prion burden/PrPSc burden; prion disease
    DOI:  https://doi.org/10.1080/15548627.2024.2410670
  2. Cell. 2024 Oct 14. pii: S0092-8674(24)01090-0. [Epub ahead of print]
    IRE1α silences dsRNA to prevent taxane-induced pyroptosis in triple-negative breast cancer.
    Longyong Xu, Fanglue Peng, Qin Luo, Yao Ding, Fei Yuan, Liting Zheng, Wei He, Sophie S Zhang, Xin Fu, Jin Liu, Ayse Sena Mutlu, Shuyue Wang, Ralf Bernd Nehring, Xingyu Li, Qianzi Tang, Catherine Li, Xiangdong Lv, Lacey E Dobrolecki, Weijie Zhang, Dong Han, Na Zhao, Eric Jaehnig, Jingyi Wang, Weiche Wu, Davis A Graham, Yumei Li, Rui Chen, Weiyi Peng, Yiwen Chen, Andre Catic, Zhibin Zhang, Bing Zhang, Anthony M Mustoe, Albert C Koong, George Miles, Michael T Lewis, Meng C Wang, Susan M Rosenberg, Bert W O'Malley, Thomas F Westbrook, Han Xu, Xiang H-F Zhang, C Kent Osborne, Jin Billy Li, Matthew J Ellis, Mothaffar F Rimawi, Jeffrey M Rosen, Xi Chen.
      Chemotherapy is often combined with immune checkpoint inhibitor (ICIs) to enhance immunotherapy responses. Despite the approval of chemo-immunotherapy in multiple human cancers, many immunologically cold tumors remain unresponsive. The mechanisms determining the immunogenicity of chemotherapy are elusive. Here, we identify the ER stress sensor IRE1α as a critical checkpoint that restricts the immunostimulatory effects of taxane chemotherapy and prevents the innate immune recognition of immunologically cold triple-negative breast cancer (TNBC). IRE1α RNase silences taxane-induced double-stranded RNA (dsRNA) through regulated IRE1-dependent decay (RIDD) to prevent NLRP3 inflammasome-dependent pyroptosis. Inhibition of IRE1α in Trp53-/- TNBC allows taxane to induce extensive dsRNAs that are sensed by ZBP1, which in turn activates NLRP3-GSDMD-mediated pyroptosis. Consequently, IRE1α RNase inhibitor plus taxane converts PD-L1-negative, ICI-unresponsive TNBC tumors into PD-L1high immunogenic tumors that are hyper-sensitive to ICI. We reveal IRE1α as a cancer cell defense mechanism that prevents taxane-induced danger signal accumulation and pyroptotic cell death.
    Keywords:  ER stress; IRE1α; PD-L1-negative breast cancer; dsRNA; pyroptosis
    DOI:  https://doi.org/10.1016/j.cell.2024.09.032
  3. Biochem Biophys Res Commun. 2024 Oct 11. pii: S0006-291X(24)01363-9. [Epub ahead of print]735 150827
    ER stress aggravates NOD1-mediated inflammatory response leading to impaired nutrient metabolism in hepatoma cells.
    Farah Gulzar, Nikita Chhikara, Pawan Kumar, Shadab Ahmad, Shubhi Yadav, Jiaur R Gayen, Akhilesh K Tamrakar.
      Nucleotide-binding Oligomerization Domain 1 (NOD1) is a cytosolic pattern recognition receptor that senses specific bacterial peptidoglycan moieties, leading to the induction of inflammatory response. Besides, sensing peptidoglycan, NOD1 has been reported to sense metabolic disturbances including the ER stress-induced unfolded protein response (UPR). However, the underpinning crosstalk between the NOD1 activating microbial ligands and the metabolic cues to alter metabolic response is not yet comprehensively defined. Here, we show that underlying ER stress aggravated peptidoglycan-induced NOD1-mediated inflammatory response in hepatoma cells. The HepG2 cells, undergoing ER stress induced by thapsigargin exhibited an amplified inflammatory response induced by peptidoglycan ligand of NOD1 (i.e. iE-DAP). This aggravated inflammatory response disrupted lipid and glucose metabolism, characterized by de novo lipogenic response, and increased gluconeogenesis in HepG2 cells. Further, we characterized that the aggravation of NOD1-induced inflammatory response was dependent on inositol-requiring enzyme 1-α (IRE1-α) and protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) activation, in conjunction with calcium flux. Altogether, our findings suggest that differential UPR activation makes liver cells more sensitive towards bacterial-derived ligands to pronounce inflammatory response in a NOD1-dependent manner that impairs hepatic nutrient metabolism.
    Keywords:  ER stress; Hepatic homeostasis; Inflammation; NOD; Nutrient metabolism
    DOI:  https://doi.org/10.1016/j.bbrc.2024.150827
  4. Nat Commun. 2024 Oct 15. 15(1): 8895
    Targeting IRE1α reprograms the tumor microenvironment and enhances anti-tumor immunity in prostate cancer.
    Bilal Unal, Omer Faruk Kuzu, Yang Jin, Daniel Osorio, Wanja Kildal, Manohar Pradhan, Sonia H Y Kung, Htoo Zarni Oo, Mads Daugaard, Mikkel Vendelbo, John B Patterson, Martin Kristian Thomsen, Marieke Lydia Kuijjer, Fahri Saatcioglu.
      Unfolded protein response (UPR) is a central stress response pathway that is hijacked by tumor cells for their survival. Here, we find that IRE1α signaling, one of the canonical UPR arms, is increased in prostate cancer (PCa) patient tumors. Genetic or small molecule inhibition of IRE1α in syngeneic mouse PCa models and an orthotopic model decreases tumor growth. IRE1α ablation in cancer cells potentiates interferon responses and activates immune system related pathways in the tumor microenvironment (TME). Single-cell RNA-sequencing analysis reveals that targeting IRE1α in cancer cells reduces tumor-associated macrophage abundance. Consistently, the small molecule IRE1α inhibitor MKC8866, currently in clinical trials, reprograms the TME and enhances anti-PD-1 therapy. Our findings show that IRE1α signaling not only promotes cancer cell growth and survival but also interferes with anti-tumor immunity in the TME. Thus, targeting IRE1α can be a promising approach for improving anti-PD-1 immunotherapy in PCa.
    DOI:  https://doi.org/10.1038/s41467-024-53039-1
  5. Biochem Biophys Res Commun. 2024 Oct 12. pii: S0006-291X(24)01365-2. [Epub ahead of print]735 150829
    Upadacitinib counteracts hepatic lipid deposition via the repression of JAK1/STAT3 signaling and AMPK/autophagy-mediated suppression of ER stress.
    Sung Ho Ahn, Yong-Jik Lee, Do Su Lim, Wonjun Cho, Hyeon Ji Gwon, A M Abd El-Aty, Ji Hoon Jeong, Tae Woo Jung.
      Upadacitinib (UPA) has been utilized to treat conditions such as rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, ulcerative colitis, Crohn's disease, ankylosing spondylitis, and axial spondyloarthritis by modulating inflammation via the JAK pathway. However, its impact on hepatic lipogenesis remains insufficiently studied. This research evaluated protein expression through Western blotting, lipid accumulation with oil red O staining, autophagosomes in hepatocytes via MDC staining, and hepatic apoptosis via cell viability and caspase 3 activity assays. This study aimed to explore the effects of UPA on hepatic lipogenesis and the underlying molecular mechanisms in in vitro models of hepatic steatosis. These findings demonstrated that UPA reduced lipid deposition, apoptosis, and ER stress in palmitate-treated hepatocytes. UPA treatment inhibited phosphorylated JAK1 and STAT3 while promoting the expression of phosphorylated AMPK and autophagy markers. AMPK siRNA negated the effects of UPA on lipogenic lipid deposition, apoptosis, JAK1/STAT3 phosphorylation, and ER stress. These results reveal that UPAmitigates ER stress through the JAK1/STAT3/AMPK pathway, thereby reducing lipid deposition and apoptosis in hyperlipidemic hepatocytes, supporting its potential as a therapeutic strategy for treating hepatic steatosis in obese individuals.
    Keywords:  AMPK; Apoptosis; ER stress; NAFLD; Steatosis; Upadacitinib
    DOI:  https://doi.org/10.1016/j.bbrc.2024.150829
  6. Proc Natl Acad Sci U S A. 2024 Oct 22. 121(43): e2403906121
    The neurotrophic factor MANF regulates autophagy and lysosome function to promote proteostasis in Caenorhabditis elegans.
    Shane K B Taylor, Jessica H Hartman, Bhagwati P Gupta.
      The conserved mesencephalic astrocyte-derived neurotrophic factor (MANF) is known for protecting dopaminergic neurons and functioning in various other tissues. Previously, we showed that Caenorhabditis elegans manf-1 null mutants exhibit defects such as increased endoplasmic reticulum (ER) stress, dopaminergic neurodegeneration, and abnormal protein aggregation. These findings suggest an essential role for MANF in cellular processes. However, the mechanisms by which intracellular and extracellular MANF regulate broader cellular functions remain unclear. We report a unique mechanism of action for MANF-1 that involves the transcription factor HLH-30/TFEB-mediated signaling to regulate autophagy and lysosomal function. Multiple transgenic strains overexpressing MANF-1 showed extended lifespan of animals, reduced protein aggregation, and improved neuronal survival. Using fluorescently tagged MANF-1, we observed tissue-specific localization of the protein, which was dependent on the ER retention signal. Further subcellular analysis showed that MANF-1 localizes within cells to the lysosomes and utilizes the endosomal pathway. Consistent with the lysosomal localization, our transcriptomic study of MANF-1 and analyses of autophagy regulators demonstrated that MANF-1 promotes proteostasis by regulating autophagic flux and lysosomal activity. Collectively, our findings establish MANF as a critical regulator of stress response, proteostasis, and aging.
    Keywords:  ER stress; MANF-1; longevity; nematode; proteostasis
    DOI:  https://doi.org/10.1073/pnas.2403906121
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