bims-unfpre Biomed News
on Unfolded protein response
Issue of 2019‒06‒16
seven papers selected by
Susan Logue
University of Manitoba

  1. FASEB J. 2019 Jun 14. fj201801240RR
    Ricci D, Marrocco I, Blumenthal D, Dibos M, Eletto D, Vargas J, Boyle S, Iwamoto Y, Chomistek S, Paton JC, Paton AW, Argon Y.
      The sensors of the unfolded protein response react to endoplasmic reticulum (ER) stress by transient activation of their enzymatic activities, which initiate various signaling cascades. In addition, the sensor IRE1α exhibits stress-induced clustering in a transient time frame similar to activation of its endoRNase activity. Previous work had suggested that the clustering response and RNase activity of IRE1α are functionally linked, but here we show that they are independent of each other and have different behaviors and modes of activation. Although both clustering and the RNase activity are responsive to luminal stress conditions and to depletion of the ER chaperone binding protein, RNase-inactive IRE1α still clusters and, conversely, full RNase activity can be accomplished without clustering. The clusters formed by RNase-inactive IRE1α are much larger and persist longer than those induced by ER stress. Clustering requires autophosphorylation, and an IRE1α mutant whose RNase domain is responsive to ligands that bind the kinase domain forms yet a third type of stress-independent cluster, with distinct physical properties and half-lives. These data suggest that IRE1α clustering can follow distinct pathways upon activation of the sensor.-Ricci, D., Marrocco, I., Blumenthal, D., Dibos, M., Eletto, D., Vargas, J., Boyle, S., Iwamoto, Y., Chomistek, S., Paton, J. C., Paton, A. W., Argon, Y. Clustering of IRE1α depends on sensing ER stress but not on its RNase activity.
    Keywords:  BiP; autophosphorylation; differential ER Stress; luteolin
  2. Sci Rep. 2019 Jun 14. 9(1): 8637
    Shyu P, Ng BSH, Ho N, Chaw R, Seah YL, Marvalim C, Thibault G.
      Phospholipid homeostasis in biological membranes is essential to maintain functions of organelles such as the endoplasmic reticulum. Phospholipid perturbation has been associated to cellular stress responses. However, in most cases, the implication of membrane lipid changes to homeostatic cellular response has not been clearly defined. Previously, we reported that Saccharomyces cerevisiae adapts to lipid bilayer stress by upregulating several protein quality control pathways such as the endoplasmic reticulum-associated degradation (ERAD) pathway and the unfolded protein response (UPR). Surprisingly, we observed certain ER-resident transmembrane proteins, which form part of the UPR programme, to be destabilised under lipid bilayer stress. Among these, the protein translocon subunit Sbh1 was prematurely degraded by membrane stiffening at the ER. Moreover, our findings suggest that the Doa10 complex recognises free Sbh1 that becomes increasingly accessible during lipid bilayer stress, perhaps due to the change in ER membrane properties. Premature removal of key ER-resident transmembrane proteins might be an underlying cause of chronic ER stress as a result of lipid bilayer stress.
  3. J Virol. 2019 Jun 12. pii: JVI.00887-19. [Epub ahead of print]
    Wang Q, Xin X, Wang T, Wan J, Ou Y, Yang Z, Yu Q, Zhu L, Guo Y, Wu Y, Ding Z, Zhang Y, Pan Z, Tang Y, Li S, Kong L.
      Accumulated evidence demonstrates that Japanese encephalitis virus (JEV) infection triggers endoplasmic reticulum (ER) stress and neuron apoptosis. ER stress sensor protein kinase R-like endoplasmic reticulum kinase (PERK) has been reported to induce apoptosis under acute or prolonged ER stress. However, the precise role of PERK in JEV-induced apoptosis and encephalitis remains unknown. Here, we reported that JEV infection activates the PERK-ATF4-CHOP apoptosis pathway both in vitro and in vivo. PERK activation also promotes the formation of stress granule, which in turn represses JEV-induced apoptosis. However, PERK inhibitor reduces apoptosis, indicating that JEV-activated PERK predominantly induces apoptosis via the PERK-ATF4-CHOP apoptosis pathway. Among JEV proteins that have been reported to induce ER stress, only JEV NS4B can induce PERK activation. PERK has been reported to form an active molecule by dimerization. The coimmunoprecipitation assay shows that NS4B interacts with PERK. Moreover, glycerol gradient centrifugation shows that NS4B induces PERK dimerization. Both the LIG-FHA and LIG-WD40 domains within NS4B are required to induce PERK dimerization, suggesting that JEV NS4B pulls two PERK molecules together by simultaneously interacting with them via different motifs. PERK deactivation reduces brain cell damage and encephalitis during JEV infection. Furthermore, expression of JEV NS4B is sufficient to induce encephalitis via PERK in mice, indicating that JEV activates PERK primarily via its NS4B to cause encephalitis. Taken together, our findings provide a novel insight into JEV-caused encephalitis.ImportanceJapanese encephalitis virus (JEV) infection triggers endoplasmic reticulum (ER) stress and neuron apoptosis. ER stress sensor protein kinase R-like endoplasmic reticulum kinase (PERK) has been reported to induce apoptosis under acute or prolonged ER stress. However, whether the PERK pathway of ER stress response plays important roles in JEV-induced apoptosis and encephalitis remains unknown. Here, we found that JEV infection activates ER stress sensor PERK in neuronal cells and mouse brains. PERK activation induces apoptosis via the PERK-ATF4-CHOP apoptosis pathway upon JEV infection. Among the JEV proteins including prM, E, NS1, NS2A, NS2B and NS4B, only NS4B activates PERK. Moreover, activated PERK participates in apoptosis and encephalitis induced by JEV and NS4B. These findings provide a novel therapeutic approach for JEV-caused encephalitis.
  4. EMBO J. 2019 Jun 13. pii: e100999. [Epub ahead of print]
    Takeda K, Nagashima S, Shiiba I, Uda A, Tokuyama T, Ito N, Fukuda T, Matsushita N, Ishido S, Iwawaki T, Uehara T, Inatome R, Yanagi S.
      Unresolved endoplasmic reticulum (ER) stress shifts the unfolded protein response signaling from cell survival to cell death, although the switching mechanism remains unclear. Here, we report that mitochondrial ubiquitin ligase (MITOL/MARCH5) inhibits ER stress-induced apoptosis through ubiquitylation of IRE1α at the mitochondria-associated ER membrane (MAM). MITOL promotes K63-linked chain ubiquitination of IRE1α at lysine 481 (K481), thereby preventing hyper-oligomerization of IRE1α and regulated IRE1α-dependent decay (RIDD). Therefore, under ER stress, MITOL depletion or the IRE1α mutant (K481R) allows for IRE1α hyper-oligomerization and enhances RIDD activity, resulting in apoptosis. Similarly, in the spinal cord of MITOL-deficient mice, ER stress enhances RIDD activity and subsequent apoptosis. Notably, unresolved ER stress attenuates IRE1α ubiquitylation, suggesting that this directs the apoptotic switch of IRE1α signaling. Our findings suggest that mitochondria regulate cell fate under ER stress through IRE1α ubiquitylation by MITOL at the MAM.
    Keywords:  IRE1α; apoptosis; mitochondrial E3 ligase MITOL/MARCH5; mitochondria‐associated ER membrane; unfolded protein response
  5. Biochim Biophys Acta Mol Cell Biol Lipids. 2019 Jun 05. pii: S1388-1981(19)30094-0. [Epub ahead of print]
    Bennett MK, Wallington-Beddoe CT, Pitson SM.
      The unfolded protein response (UPR) is a response by the endoplasmic reticulum to stress, classically caused by any disruption to cell homeostasis that results in an accumulation in unfolded proteins. However, there is an increasing body of research demonstrating that the UPR can also be activated by changes in lipid homeostasis, including changes in sphingolipid metabolism. Sphingolipids are a family of bioactive lipids with important roles in both the formation and integrity of cellular membranes, and regulation of key cellular processes, including cell proliferation and apoptosis. Bi-directional interactions between sphingolipids and the UPR have now been observed in a range of diseases, including cancer, diabetes and liver disease. Determining how these two key cellular components influence each other could play an important role in deciphering the causes of these diseases and potentially reveal new therapeutic approaches.
    Keywords:  Ceramide; Endoplasmic reticulum stress; Sphingolipids; Unfolded protein response
  6. Cell Stress Chaperones. 2019 Jun 10.
    Lee J, Hong SW, Kwon H, Park SE, Rhee EJ, Park CY, Oh KW, Park SW, Lee WY.
      Endoplasmic reticulum stress (ER stress) is involved in lipid metabolism and lipotoxicity and can lead to apoptosis. Resveratrol, a sirtuin 1 (SIRT1) agonist, prevents ER stress and improves ER stress-induced hepatic steatosis and cell death. Clusterin is a secreted chaperone and has roles in various physiological processes. However, changes in the expression of clusterin upon ER stress and the connection between SIRT1 and clusterin in protection against ER stress are not well known. In cells treated with tunicamycin, resveratrol increased the expression of clusterin mRNA and protein and the secreted clusterin protein level in conditioned medium. Resveratrol decreased protein expression of the ER stress markers, p-PERK, p-IRE1α, and CHOP, and increased the expression of the ER-associated degradation (ERAD) factors, SEL1L and HRD1, in tunicamycin-treated cells. However, no changes in the expression of these genes were observed in clusterin siRNA-transfected cells. Moreover, increased LAMP2 and LC3 expression and decreased Rubicon expression were observed in cells treated with resveratrol or secreted clusterin. These data suggest that SIRT1 activation by resveratrol attenuates ER stress by promoting protective processes such as ERAD and autophagy pathways and that these protective effects are mediated by clusterin.
    Keywords:  Autophagy; Chaperone; Clusterin; ER stress; ERAD; SIRT1
  7. Circulation. 2019 Jun 10.
    Wang X, Deng Y, Zhang G, Li C, Ding G, May HI, Tran DH, Luo X, Jiang DS, Li DL, Wei X, Xu L, Ferdous A, Gillette TG, Scherer PE, Jiang X, Wang ZV.
      BACKGROUND: The unfolded protein response (UPR) plays versatile roles in physiology and pathophysiology. Its connection to cell growth however remains elusive. Here, we sought to define the role of UPR in regulation of cardiomyocyte growth in the heart.METHODS: We used both gain- and loss-of-function approaches to genetically manipulate spliced X-box binding protein 1 (XBP1s), the most conserved signaling branch of the UPR, in the heart. In addition, primary cardiomyocyte culture was employed to address the role of XBP1s in cell growth in a cell-autonomous manner.
    RESULTS: We found that XBP1s expression is reduced in both human and rodent cardiac tissues under heart failure. Further, deficiency of XBP1s leads to decompensation and exacerbation of heart failure progression under pressure overload. On the other hand, cardiac-restricted overexpression of XBP1s prevents the development of cardiac dysfunction. Mechanistically, we found that XBP1s stimulates adaptive cardiac growth through activation of the mechanistic target of rapamycin (mTOR) signaling, which is mediated via FK506-binding protein 11 (FKBP11), a novel transcriptional target of XBP1s. Moreover, silencing of FKBP11 significantly diminishes XBP1s-induced mTOR activation and adaptive cell growth.
    CONCLUSIONS: Our results reveal a critical role of the XBP1s-FKBP11-mTOR axis in coupling the UPR and cardiac cell growth regulation.
    Keywords:  FKBP11; XBP1s; mTOR; unfolded protein response