bims-ershed Biomed News
on ER Stress in Health and Diseases
Issue of 2021‒11‒28
six papers selected by
Matías Eduardo González Quiroz
Worker’s Hospital

  1. Cells. 2021 Oct 31. pii: 2965. [Epub ahead of print]10(11):
      The endoplasmic reticulum (ER) is the major site of membrane biogenesis in most eukaryotic cells. As the entry point to the secretory pathway, it handles more than 10,000 different secretory and membrane proteins. The insertion of proteins into the membrane, their folding, and ER exit are affected by the lipid composition of the ER membrane and its collective membrane stiffness. The ER is also a hotspot of lipid biosynthesis including sterols, glycerophospholipids, ceramides and neural storage lipids. The unfolded protein response (UPR) bears an evolutionary conserved, dual sensitivity to both protein-folding imbalances in the ER lumen and aberrant compositions of the ER membrane, referred to as lipid bilayer stress (LBS). Through transcriptional and non-transcriptional mechanisms, the UPR upregulates the protein folding capacity of the ER and balances the production of proteins and lipids to maintain a functional secretory pathway. In this review, we discuss how UPR transducers sense unfolded proteins and LBS with a particular focus on their role as guardians of the secretory pathway.
    Keywords:  ATF6; ER; IRE1; PERK; UPR; hydrophobic mismatch; lipid bilayer stress; membrane stiffness; membrane thickness; proteotoxic stress; secretory pathway
  2. J Invest Dermatol. 2021 Nov 19. pii: S0022-202X(21)02508-2. [Epub ahead of print]
      The unfolded protein response is activated by UVB irradiation, but the role of a key mediator, inositol requiring enzyme 1a (IRE1α), is not clear. Here, we show that mice with an epidermal IRE1α deletion are sensitized to UV with increased apoptosis, rapid loss of UV-induced cyclopyrimidine dimer (CPD) positive keratinocytes and sloughing of the epidermis. In vitro, IRE1α deficient keratinocytes have increased UVB sensitivity, reduced CPD repair and reduced accumulation of γH2AX and p-ATR, suggesting defective the activation of nucleotide excision repair. Knockdown of XBP1 or pharmacological inhibition of the IRE1α RNase did not phenocopy IRE1α deficiency. The altered UV response was linked to elevated intracellular calcium levels and ROS, and this was due to dysregulation of the ER calcium channel inositol triphosphate receptor (InsP3R). Pharmacologic, genetic, and biochemical studies linked regulation of the Ins3PR, intracellular calcium and normal UV DNA damage response to calcium and integrin binding protein 1 (CIB1) and the IRE1α-TRAF2-ASK1 complex. These results suggest a model where IRE1α activation state drives CIB1 binding either to the InsP3R or ASK1 to regulate ER calcium efflux, ROS and DNA repair responses following UV.
    Keywords:  DNA damage response; ER stress; IRE1α; Intracellular calcium; Skin; UVB; Unfolded Protein Response
  3. Front Med (Lausanne). 2021 ;8 758311
      The endoplasmic reticulum (ER) is not only responsible for protein synthesis and folding but also plays a critical role in sensing cellular stress and maintaining cellular homeostasis. Upon sensing the accumulation of unfolded proteins due to perturbation in protein synthesis or folding, specific intracellular signaling pathways are activated, which are collectively termed as unfolded protein response (UPR). UPR expands the capacity of the protein folding machinery, decreases protein synthesis and enhances ER-associated protein degradation (ERAD) which degrades misfolded proteins through the proteasomes. More recent evidences suggest that UPR also amplifies cytokines-mediated inflammatory responses leading to pathogenesis of inflammatory diseases. UPR signaling also activates autophagy; a lysosome-dependent degradative pathwaythat has an extended capacity to degrade misfolded proteins and damaged ER. Thus, activation of autophagy limits inflammatory response and provides cyto-protection by attenuating ER-stress. Here we review the mechanisms that couple UPR, autophagy and cytokine-induced inflammation that can facilitate the development of novel therapeutic strategies to mitigate cellular stress and inflammation associated with various pathologies.
    Keywords:  ER-stress; autophagy; cytokines; inflammation; unfolded protein response
  4. Elife. 2021 Nov 23. pii: e73215. [Epub ahead of print]10
      Skeletal muscle regeneration is regulated by coordinated activation of multiple signaling pathways activated in both injured myofibers and satellite cells. The unfolded protein response (UPR) is a major mechanism that detects and alleviates protein-folding stresses in ER. However, the role of individual arms of the UPR in skeletal muscle regeneration remain less understood. In the present study, we demonstrate that IRE1α (also known as ERN1) and its downstream target, XBP1, are activated in skeletal muscle of mice upon injury. Myofiber-specific ablation of IRE1 or XBP1 in mice diminishes skeletal muscle regeneration that is accompanied with reduced number of satellite cells and their fusion to injured myofibers. Ex vivo cultures of myofiber explants demonstrate that ablation of IRE1α reduces the proliferative capacity of myofiber-associated satellite cells. Myofiber-specific deletion of IRE1α dampens Notch signaling and canonical NF-kB pathway in skeletal muscle of mice. Our results also demonstrate that targeted ablation of IRE1α reduces skeletal muscle regeneration in the mdx mice, a model of Duchenne muscular dystrophy. Collectively, our results reveal that the IRE1α-mediated signaling promotes muscle regeneration through augmenting the proliferation of satellite cells in a cell non-autonomous manner.
    Keywords:  cell biology; mouse; regenerative medicine; stem cells
  5. Sci China Life Sci. 2021 Nov 19.
      Although the functional parameters of microRNAs (miRNAs) have been explored to some extent, the roles of these molecules in coronavirus infection and the regulatory mechanism of miRNAs in virus infection are still unclear. Transmissible gastroenteritis virus (TGEV) is an enteropathgenic coronavirus and causes high morbidity and mortality in suckling piglets. Here, we demonstrated that microRNA-27b-3p (miR-27b-3p) suppressed TGEV replication by directly targeting porcine suppressor of cytokine signaling 6 (SOCS6), while TGEV infection downregulated miR-27b-3p expression in swine testicular (ST) cells and in piglets. Mechanistically, the decrease of miR-27b-3p expression during TGEV infection was mediated by the activated inositol-requiring enzyme 1 (IRE1) pathway of the endoplasmic reticulum (ER) stress. Further studies showed that when ER stress was induced by TGEV, IRE1 acted as an RNase activated by autophosphorylation and unconventionally spliced mRNA encoding a potent transcription factor, X-box-binding protein 1 (Xbp1s). Xbp1s inhibited the transcription of miR-27 and ultimately reduced the production of miR-27b-3p. Therefore, our findings indicate that TGEV inhibits the expression of an anti-coronavirus microRNA through the IRE1 pathway and suggest a novel way in which coronavirus regulates the host cell response to infection.
    Keywords:  coronavirus; immune evasion; inositol-requiring enzyme 1 (IRE1); microRNA; transmissible gastroenteritis coronavirus (TGEV)
  6. Cells. 2021 Nov 18. pii: 3216. [Epub ahead of print]10(11):
      Numerous cellular processes are controlled by the proteasome, a multicatalytic protease in the cytosol and nucleus of all eukaryotic cells, through regulated protein degradation. The immunoproteasome is a special type of proteasome which is inducible under inflammatory conditions and constitutively expressed in hematopoietic cells. MECL-1 (β2i), LMP2 (β1i), and LMP7 (β5i) are the proteolytically active subunits of the immunoproteasome (IP), which is known to shape the antigenic repertoire presented on major histocompatibility complex (MHC) class I molecules. Furthermore, the immunoproteasome is involved in T cell expansion and inflammatory diseases. In recent years, targeting the immunoproteasome in cancer, autoimmune diseases, and transplantation proved to be therapeutically effective in preclinical animal models. However, the prime function of standard proteasomes and immunoproteasomes is the control of protein homeostasis in cells. To maintain protein homeostasis in cells, proteasomes remove proteins which are not properly folded, which are damaged by stress conditions such as reactive oxygen species formation, or which have to be degraded on the basis of regular protein turnover. In this review we summarize the latest insights on how the immunoproteasome influences protein homeostasis.
    Keywords:  immunoproteasome; proteasome; proteasome inhibition; protein degradation; protein homeostasis; proteotoxic stress; ubiquitin; ubiquitin–proteasome system (UPS); unfolded protein response (UPR)