bims-unfpre Biomed News
on Unfolded protein response
Issue of 2019‒08‒04
four papers selected by
Susan Logue
University of Manitoba


  1. Proc Natl Acad Sci U S A. 2019 Aug 01. pii: 201906999. [Epub ahead of print]
    Harnoss JM, Le Thomas A, Shemorry A, Marsters SA, Lawrence DA, Lu M, Chen YA, Qing J, Totpal K, Kan D, Segal E, Merchant M, Reichelt M, Ackerly Wallweber H, Wang W, Clark K, Kaufman S, Beresini MH, Laing ST, Sandoval W, Lorenzo M, Wu J, Ly J, De Bruyn T, Heidersbach A, Haley B, Gogineni A, Weimer RM, Lee D, Braun MG, Rudolph J, VanWyngarden MJ, Sherbenou DW, Gomez-Bougie P, Amiot M, Acosta-Alvear D, Walter P, Ashkenazi A.
      Multiple myeloma (MM) arises from malignant immunoglobulin (Ig)-secreting plasma cells and remains an incurable, often lethal disease despite therapeutic advances. The unfolded-protein response sensor IRE1α supports protein secretion by deploying a kinase-endoribonuclease module to activate the transcription factor XBP1s. MM cells may co-opt the IRE1α-XBP1s pathway; however, the validity of IRE1α as a potential MM therapeutic target is controversial. Genetic disruption of IRE1α or XBP1s, or pharmacologic IRE1α kinase inhibition, attenuated subcutaneous or orthometastatic growth of MM tumors in mice and augmented efficacy of two established frontline antimyeloma agents, bortezomib and lenalidomide. Mechanistically, IRE1α perturbation inhibited expression of key components of the endoplasmic reticulum-associated degradation machinery, as well as secretion of Ig light chains and of cytokines and chemokines known to promote MM growth. Selective IRE1α kinase inhibition reduced viability of CD138+ plasma cells while sparing CD138- cells derived from bone marrows of newly diagnosed or posttreatment-relapsed MM patients, in both US- and European Union-based cohorts. Effective IRE1α inhibition preserved glucose-induced insulin secretion by pancreatic microislets and viability of primary hepatocytes in vitro, as well as normal tissue homeostasis in mice. These results establish a strong rationale for developing kinase-directed inhibitors of IRE1α for MM therapy.
    Keywords:  endoplasmic reticulum stress; inositol-requiring enzyme 1; kinase inhibitors; multiple myeloma; unfolded protein response
    DOI:  https://doi.org/10.1073/pnas.1906999116
  2. EMBO J. 2019 Aug 01. 38(15): e100999
    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; mitochondria-associated ER membrane; mitochondrial E3 ligase MITOL/MARCH5; unfolded protein response
    DOI:  https://doi.org/10.15252/embj.2018100999
  3. EMBO J. 2019 Aug 01. 38(15): e100990
    Oka OB, van Lith M, Rudolf J, Tungkum W, Pringle MA, Bulleid NJ.
      Activation of the ATF6α signaling pathway is initiated by trafficking of ATF6α from the ER to the Golgi apparatus. Its subsequent proteolysis releases a transcription factor that translocates to the nucleus causing downstream gene activation. How ER retention, Golgi trafficking, and proteolysis of ATF6α are regulated and whether additional protein partners are required for its localization and processing remain unresolved. Here, we show that ER-resident oxidoreductase ERp18 associates with ATF6α following ER stress and plays a key role in both trafficking and activation of ATF6α. We find that ERp18 depletion attenuates the ATF6α stress response. Paradoxically, ER stress accelerates trafficking of ATF6α to the Golgi in ERp18-depleted cells. However, the translocated ATF6α becomes aberrantly processed preventing release of the soluble transcription factor. Hence, we demonstrate that ERp18 monitors ATF6α ER quality control to ensure optimal processing following trafficking to the Golgi.
    Keywords:  ATF6α; ER stress; ERp18; protein trafficking; unfolded protein response
    DOI:  https://doi.org/10.15252/embj.2018100990
  4. Mol Cell. 2019 Jul 08. pii: S1097-2765(19)30485-X. [Epub ahead of print]
    Ji CH, Kim HY, Heo AJ, Lee SH, Lee MJ, Kim SB, Srinivasrao G, Mun SR, Cha-Molstad H, Ciechanover A, Choi CY, Lee HG, Kim BY, Kwon YT.
      The endoplasmic reticulum (ER) is susceptible to wear-and-tear and proteotoxic stress, necessitating its turnover. Here, we show that the N-degron pathway mediates ER-phagy. This autophagic degradation initiates when the transmembrane E3 ligase TRIM13 (also known as RFP2) is ubiquitinated via the lysine 63 (K63) linkage. K63-ubiquitinated TRIM13 recruits p62 (also known as sequestosome-1), whose complex undergoes oligomerization. The oligomerization is induced when the ZZ domain of p62 is bound by the N-terminal arginine (Nt-Arg) of arginylated substrates. Upon activation by the Nt-Arg, oligomerized TRIM13-p62 complexes are separated along with the ER compartments and targeted to autophagosomes, leading to lysosomal degradation. When protein aggregates accumulate within the ER lumen, degradation-resistant autophagic cargoes are co-segregated by ER membranes for lysosomal degradation. We developed synthetic ligands to the p62 ZZ domain that enhance ER-phagy for ER protein quality control and alleviate ER stresses. Our results elucidate the biochemical mechanisms and pharmaceutical means that regulate ER homeostasis.
    Keywords:  ER homeostasis; ER protein quality control; ER stress response; ER-phagy; N-degron pathway; N-terminal arginylation; TRIM13; endoplasmic reticulum; p62; ubiquitination; α1-antitrypsin deficiency
    DOI:  https://doi.org/10.1016/j.molcel.2019.06.028