bims-unfpre Biomed News
on Unfolded protein response
Issue of 2021–10–03
nine papers selected by
Susan Logue, University of Manitoba
  1. The stress-sensing domain of activated IRE1α forms helical filaments in narrow ER membrane tubes.
  2. Activated PI3Kδ signals compromise plasma cell survival via limiting autophagy and increasing ER stress.
  3. Integrated Stress Response Couples Mitochondrial Protein Translation with Oxidative Stress Control.
  4. Downregulation of activating transcription factor 4 attenuates lysophosphatidycholine-induced inflammation via the NF-κB pathway.
  5. TMBIM6 regulates redox-associated posttranslational modifications of IRE1α and ER stress response failure in aging mice and humans.
  6. HSPB1 Is Essential for Inducing Resistance to Proteotoxic Stress in Beta-Cells.
  7. ER stress promotes HBV production by enhancing utilization of the autophagosome- multivesicular body axis.
  8. MFN2 Stabilization: A Bridge for Endoplasmic Reticulum Stress Sensitivity in Melanoma.
  9. Heat Shock Factor 1 Prevents Age-Related Hearing Loss by Decreasing Endoplasmic Reticulum Stress.
  1. Science. 2021 Oct;374(6563): 52-57
    The stress-sensing domain of activated IRE1α forms helical filaments in narrow ER membrane tubes.
    Ngoc-Han Tran, Stephen D Carter, Ann De Mazière, Avi Ashkenazi, Judith Klumperman, Peter Walter, Grant J Jensen.
      [Figure: see text].
    DOI:  https://doi.org/10.1126/science.abh2474
  2. J Exp Med. 2021 Dec 06. pii: e20211035. [Epub ahead of print]218(12):
    Activated PI3Kδ signals compromise plasma cell survival via limiting autophagy and increasing ER stress.
    Fahd Al Qureshah, Sara Sagadiev, Christopher D Thouvenel, Shuozhi Liu, Zhaolin Hua, Baidong Hou, Mridu Acharya, Richard G James, David J Rawlings.
      While phosphatidylinositide 3-kinase delta (PI3Kδ) plays a critical role in humoral immunity, the requirement for PI3Kδ signaling in plasma cells remains poorly understood. Here, we used a conditional mouse model of activated PI3Kδ syndrome (APDS), to interrogate the function of PI3Kδ in plasma cell biology. Mice expressing a PIK3CD gain-of-function mutation (aPIK3CD) in B cells generated increased numbers of memory B cells and mounted an enhanced secondary response but exhibited a rapid decay of antibody levels over time. Consistent with these findings, aPIK3CD expression markedly impaired plasma cell generation, and expression of aPIK3CD intrinsically in plasma cells was sufficient to diminish humoral responses. Mechanistically, aPIK3CD disrupted ER proteostasis and autophagy, which led to increased plasma cell death. Notably, this defect was driven primarily by elevated mTORC1 signaling and modulated by treatment with PI3Kδ-specific inhibitors. Our findings establish an essential role for PI3Kδ in plasma cell homeostasis and suggest that modulating PI3Kδ activity may be useful for promoting and/or thwarting specific immune responses.
    DOI:  https://doi.org/10.1084/jem.20211035
  3. Circulation. 2021 Sep 29.
    Integrated Stress Response Couples Mitochondrial Protein Translation with Oxidative Stress Control.
    Guangyu Zhang, Xiaoding Wang, Chao Li, Qinfeng Li, Yu A An, Xiang Luo, Yingfeng Deng, Thomas G Gillette, Philipp E Scherer, Zhao V Wang.
      Background: The integrated stress response (ISR) is an evolutionarily conserved process to cope with intracellular and extracellular disturbances. Myocardial infarction is a leading cause of death worldwide. Coronary artery reperfusion is the most effective means to mitigate cardiac damage of myocardial infarction, which however causes additional reperfusion injury. This study aimed to investigate the role of the ISR in myocardial ischemia/reperfusion (I/R). Methods: Cardiac-specific gain- and loss-of-function approaches for the ISR were employed in vivo. Myocardial I/R was achieved by the ligation of the cardiac left anterior descending artery for 45 minutes, followed by reperfusion for different times. Cardiac function was assessed by echocardiography. Additionally, cultured H9c2 cells, primary rat cardiomyocytes, and mouse embryonic fibroblasts were used to dissect underlying molecular mechanisms. Moreover, tandem mass tag (TMT) labeling and mass spectrometry was conducted to identify protein targets of the ISR. Pharmacological means were tested to manipulate the ISR for therapeutic exploration. Results: We show that the PERK/eIF2α axis of the ISR is strongly induced by I/R in cardiomyocytes in vitro and in vivo. We further reveal a physiological role of PERK/eIF2α signaling by showing that acute activation of PERK in the heart confers robust cardioprotection against reperfusion injury. In contrast, cardiac-specific deletion of PERK aggravates cardiac responses to reperfusion. Mechanistically, the ISR directly targets mitochondrial complexes via translational suppression. We identify NDUFAF2, an assembly factor of mitochondrial complex I, as a selective target of PERK. Overexpression of PERK suppresses the protein expression of NDUFAF2 while PERK inhibition causes an increase of NDUFAF2. Silencing of NDUFAF2 significantly rescues cardiac cell survival from PERK knockdown under I/R. Further, we show that activation of PERK/eIF2α signaling reduces mitochondrial complex-derived reactive oxygen species and improves cardiac cell survival in response to I/R. Moreover, pharmacological stimulation of the ISR protects the heart against reperfusion damage, even after the restoration of occluded coronary artery, highlighting a clinical relevance for myocardial infarction treatment. Conclusions: These studies suggest that the ISR improves cell survival and mitigate reperfusion damage by selectively suppressing mitochondrial protein synthesis and reducing oxidative stress in the heart.
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.120.053125
  4. Eur J Pharmacol. 2021 Sep 25. pii: S0014-2999(21)00611-7. [Epub ahead of print] 174457
    Downregulation of activating transcription factor 4 attenuates lysophosphatidycholine-induced inflammation via the NF-κB pathway.
    Yingchao Gong, Qingfeng Li, Zetao Ma, Tingting Jin, Jun Lin, Qingbo Lv, Meihui Wang, Guosheng Fu, Shengjie Xu.
      Lysophosphatidycholine (LPC) is the main active component in oxidized low-density lipoprotein (ox-LDL). The pathological function of ox-LDL has been broadly studied in atherosclerosis. However, the specific relationship between LPC-induced unfolded protein response (UPR) and inflammation in human umbilical vein endothelial cells (HUVECs) remains elusive. In this study, we found elevated serum levels of LPC in atherosclerotic patients. LPC stimulation resulted in elevated secretion of interleukin (IL)-6 and IL-8 in HUVECs, accompanied with the activation of ER stress and NF-κB pathway. Additionally, suppression of ER stress by 4-phenylbutric acid (4-PBA), an ER stress inhibitor, alleviated the activation of the NF-κB pathway and secretion of inflammatory factors. Moreover, activating transcription factor 4 (ATF4) silencing inhibited the transcription and secretion of IL-6 and IL-8, and suppressed the adhesion of THP-1 cells to HUVECs. Activation of the NF-κB pathway and expression of its upstream factors, including Toll like receptor 4 and cellular inhibitor of apoptosis, were also inhibited by ATF4 silencing. The present findings suggest that suppression of UPR alleviates LPC-induced HUVECs inflammation by inhibition of NF-κB pathway, and indicate ATF4 as a potential target for the treatment of atherosclerosis.
    Keywords:  ER stress; Inflammation; Lysophosphatidycholine; NF-κB pathway
    DOI:  https://doi.org/10.1016/j.ejphar.2021.174457
  5. Redox Biol. 2021 Sep 09. pii: S2213-2317(21)00287-1. [Epub ahead of print]47 102128
    TMBIM6 regulates redox-associated posttranslational modifications of IRE1α and ER stress response failure in aging mice and humans.
    Kashi Raj Bhattarai, Hyun-Kyoung Kim, Manoj Chaudhary, Mohammad Mamun Ur Rashid, Jisun Kim, Hyung-Ryong Kim, Han-Jung Chae.
      Age-associated persistent ER stress is the result of declining chaperone systems of the ER that reduces cellular functions, induces apoptosis, and leads to age-related diseases. This study investigated the previously unknown regulatory mechanism of TMBIM6 during age-associated hepatic abnormalities. Wild-type (WT) and the TMBIM6 knockout (TMBIM6-/-) mice liver, human liver samples from different age groups were used to demonstrate the effect of physiological aging on liver. For TMBIM6 rescue experiments, TMBIM6-/- old mice and stable human hepatic cell lines expressing TMBIM 6 were used to study the functional role of TMBIM6 on aging-associated steatosis and its associated mechanisms. In aging humans and mice, we observed declined expression of TMBIM6 and aberrant UPR expression, which were associated with high hepatic lipid accumulation. During aging, TMBIM6-deficient mice had increased senescence than their WT counterparts. We identified redox-mediated posttranslational modifications of IRE1α such as S-nitrosylation and sulfonation were higher in TMBIM6-deficient aging mice and humans, which impaired the ER stress response signaling. Sulfonation of IRE1α enhanced regulated IRE1α-dependent decay (RIDD) activity inducing TMBIM6 decay, whereas S-nitrosylation of IRE1α inhibited XBP1 splicing enhancing the cell death. Moreover, the degradation of miR-338-3p by strong IRE1α cleavage activity enhanced the expression of PTP1B, resulting in diminishing phosphorylation of PERK. The re-expression of TMBIM6 reduced IRE1α modifications, preserved ER homeostasis, reduced senescence and senescence-associated lipid accumulation in human hepatic cells and TMBIM6-depleted mice. S-nitrosylation or sulfonation of IRE1α and its controller, the TMBIM6, might be the potential therapeutic targets for maintaining ER homeostasis in aging and aging-associated liver diseases.
    Keywords:  Aging; ER stress response failure; IRE1α modifications; S-nitrosylation; Sulfonation; TMBIM6/BI-1
    DOI:  https://doi.org/10.1016/j.redox.2021.102128
  6. Cells. 2021 Aug 24. pii: 2178. [Epub ahead of print]10(9):
    HSPB1 Is Essential for Inducing Resistance to Proteotoxic Stress in Beta-Cells.
    Vinícius M Gomes, Rosangela A M Wailemann, Gabriel S Arini, Talita C Oliveira, Daria R Q Almeida, Ancély F Dos Santos, Letícia F Terra, Stephan Lortz, Leticia Labriola.
      During type 1 diabetes mellitus (T1DM) development, beta-cells undergo intense endoplasmic reticulum (ER) stress that could result in apoptosis through the failure of adaptation to the unfolded protein response (UPR). Islet transplantation is considered an attractive alternative among beta-cell replacement therapies for T1DM. To avoid the loss of beta-cells that will jeopardize the transplant's outcome, several strategies are being studied. We have previously shown that prolactin induces protection against proinflammatory cytokines and redox imbalance-induced beta-cell death by increasing heat-shock protein B1 (HSPB1) levels. Since the role of HSPB1 in beta cells has not been deeply studied, we investigated the mechanisms involved in unbalanced protein homeostasis caused by intense ER stress and overload of the proteasomal protein degradation pathway. We tested whether HSPB1-mediated cytoprotective effects involved UPR modulation and improvement of protein degradation via the ubiquitin-proteasome system. We demonstrated that increased levels of HSPB1 attenuated levels of pro-apoptotic proteins such as CHOP and BIM, as well as increased protein ubiquitination and the speed of proteasomal protein degradation. Our data showed that HSPB1 induced resistance to proteotoxic stress and, thus, enhanced cell survival via an increase in beta-cell proteolytic capacity. These results could contribute to generate strategies aimed at the optimization of beta-cell replacement therapies.
    Keywords:  HSPB1; apoptosis; beta-cells; cytoprotection; diabetes mellitus; endoplasmic reticulum stress; heat-shock proteins; proteostasis
    DOI:  https://doi.org/10.3390/cells10092178
  7. Hepatology. 2021 Sep 28.
    ER stress promotes HBV production by enhancing utilization of the autophagosome- multivesicular body axis.
    Xueyu Wang, Zhiqiang Wei, Bin Cheng, Jia Li, Yulin He, Tingyu Lan, Thekla Kemper, Yong Lin, Bin Jiang, Yongfang Jiang, Zhongji Meng, Mengji Lu.
       BACKGROUND & AIMS: Hepatitis B virus (HBV) infection has been reported to trigger endoplasmic reticulum (ER) stress and initiate autophagy. However, how ER stress and autophagy influence HBV production remains elusive. Here, we studied the effect of tunicamycin (TM), an N-glycosylation inhibitor and ER stress inducer, on HBV replication and secretion, and examined the underlying mechanisms.
    APPROACH & RESULTS: PDI (an ER marker), LC3 (an autophagosome marker) and p62 (a typical cargo for autophagic degradation) expression were tested in the liver tissues of patients with chronic HBV infection and hepatoma cell lines. The role of TM treatment in HBV production and trafficking was examined in hepatoma cell lines. TM treatment that mimics HBV infection triggered ER stress and increased autophagosome formation, resulting in enhanced HBV replication and the secretion of subviral particles (SVPs) and naked capsids. Additionally, TM reduced the number of early endosomes and HBV surface antigen (HBsAg) localization in this compartment, causing HBsAg/SVPs accumulate in the ER. Thus, TM-induced autophagosome formation serves as an alternative pathway for HBsAg/SVPs trafficking. Importantly, TM inhibited autophagosome-lysosome fusion, accompanied by enhanced autophagosome-late endosome/multivesicular body (MVB) fusion to release HBsAg/SVPs through or along with exosome release. Notably, TM treatment inhibited the HBsAg glycosylation, resulting in impairment of the HBV virions envelopment and secretion, but it was not critical for HBsAg/SVPs trafficking in our cell systems.
    CONCLUSIONS: TM-induced ER stress and autophagic flux promoted HBV replication and the release of SVPs and naked capsids through the autophagosome-late endosome/MVB axis.
    Keywords:  Hepatitis B virus; autophagosome; multivesicular bodies/MVBs; vesicular trafficking
    DOI:  https://doi.org/10.1002/hep.32178
  8. J Invest Dermatol. 2021 Sep 23. pii: S0022-202X(21)01224-0. [Epub ahead of print]
    MFN2 Stabilization: A Bridge for Endoplasmic Reticulum Stress Sensitivity in Melanoma.
    Charles H Adelmann, Inbal Rachmin, David E Fisher.
      In a new article in the Journal of Investigative Dermatology, Wang et al. (2021) report that mitochondrial quality control modulates responses to endoplasmic reticulum (ER) stress in melanoma. They implicate a linear pathway of XBP1, MARCH5, and MFN2 that act together to regulate mitochondrial fission and mitophagy and ultimately mediate melanoma cell sensitivity to ER stress. This work informs therapeutic combinations and biomarker strategies for targeting melanoma organellar homeostasis as well as for life‒death decisions.
    DOI:  https://doi.org/10.1016/j.jid.2021.05.003
  9. Cells. 2021 Sep 17. pii: 2454. [Epub ahead of print]10(9):
    Heat Shock Factor 1 Prevents Age-Related Hearing Loss by Decreasing Endoplasmic Reticulum Stress.
    Yun Yeong Lee, Eun Sol Gil, In Hye Jeong, Hantai Kim, Jeong Hun Jang, Yun-Hoon Choung.
      Endoplasmic reticulum (ER) stress is a common stress factor during the aging process. Heat shock factor 1 (HSF1) plays a critical role in ER stress; however, its exact function in age-related hearing loss (ARHL) has not been fully elucidated. The purpose of the present study was to identify the role of HSF1 in ARHL. In this study, we demonstrated that the loss of inner and outer hair cells and their supporting cells was predominant in the high-frequency region (basal turn, 32 kHz) in ARHL cochleae. In the aging cochlea, levels of the ER stress marker proteins p-eIF2α and CHOP increased as HSF1 protein levels decreased. The levels of various heat shock proteins (HSPs) also decreased, including HSP70 and HSP40, which were markedly downregulated, and the expression levels of Bax and cleaved caspase-3 apoptosis-related proteins were increased. However, HSF1 overexpression showed significant hearing protection effects in the high-frequency region (basal turn, 32 kHz) by decreasing CHOP and cleaved caspase-3 and increasing the HSP40 and HSP70 proteins. These findings were confirmed by HSF1 functional studies using an auditory cell model. Therefore, we propose that HSF1 can function as a mediator to prevent ARHL by decreasing ER stress-dependent apoptosis in the aging cochlea.
    Keywords:  age-related hearing loss; apoptosis; endoplasmic reticulum stress; heat shock factor 1; heat shock protein
    DOI:  https://doi.org/10.3390/cells10092454
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