bims-ershed Biomed News
on ER Stress in Health and Diseases
Issue of 2023‒07‒02
five papers selected by
Matías Eduardo González Quiroz
Worker’s Hospital
  1. Beyond UPR: Cell-specific Roles of ER Stress Sensor IRE1α in Kidney Ischemic Injury and Transplant Rejection.
  2. The Unfolded Protein Response Sensor IRE1 Regulates Activation of In Vitro Differentiated Type 1 Conventional DCs with Viral Stimuli.
  3. Interactome Analysis of the ER Stress Sensor Perk Uncovers Key Components of ER-Mitochondria Contact Sites and Ca2+ Signalling.
  4. The unfolded protein response of the endoplasmic reticulum supports mitochondrial biogenesis by buffering non-imported proteins.
  5. The transcription factor XBP1 in dendritic cells promotes the TH2 cell response in airway allergy.
  1. Kidney Int. 2023 Jun 28. pii: S0085-2538(23)00470-2. [Epub ahead of print]
    Beyond UPR: Cell-specific Roles of ER Stress Sensor IRE1α in Kidney Ischemic Injury and Transplant Rejection.
    Longhui Qiu, Xin Zheng, Dinesh Jaishankar, Richard Green, Deyu Fang, Satish Nadig, Zheng Jenny Zhang.
      Kidney damage due to ischemia or rejection results in the accumulation of unfolded and misfolded proteins in the endoplasmic reticulum (ER) lumen, a condition known as "ER stress". Inositol-requiring enzyme 1α (IRE1α), the first ER stress sensor found, is a type I transmembrane protein with kinase and endoribonuclease activity. Upon activation, IRE1α non-conventionally splices an intron from unspliced X-box binding protein 1 (XBP1u) mRNA to produce XBP1s mRNA that encodes the transcription factor, XBP1s, for the expression of genes encoding proteins that mediate the unfolded protein response (UPR). The UPR promotes the functional fidelity of ER and is required for secretory cells to sustain protein folding and secretory capability. Prolonged ER stress can lead to apoptosis, which may result in detrimental repercussions to organ health and has been implicated in the pathogenesis and progression of kidney diseases. The IRE1α-XBP1 signaling acts as a major arm of UPR and is involved in regulating autophagy, cell differentiation, and cell death. IRE1α also interacts with Activator Protein-1 (AP-1) and Nuclear Factor-κB (NF-κB) pathways to regulate inflammatory responses. Studies using transgenic mouse models highlight that the roles of IRE1α differ depending on cell type and disease setting. This review covers these cell-specific roles of IRE1α signaling and the potential for therapeutic targeting of this pathway in the context of ischemia and rejection affecting the kidneys.
    Keywords:  Acute kidney injury; Cell signaling; Cell survival; Endoplasmic reticulum; Transplantation
    DOI:  https://doi.org/10.1016/j.kint.2023.06.016
  2. Int J Mol Sci. 2023 Jun 16. pii: 10205. [Epub ahead of print]24(12):
    The Unfolded Protein Response Sensor IRE1 Regulates Activation of In Vitro Differentiated Type 1 Conventional DCs with Viral Stimuli.
    Bernardita Medel, José Ignacio Bernales, Alonso Lira, Dominique Fernández, Takao Iwawaki, Pablo Vargas, Fabiola Osorio.
      Type 1 conventional dendritic cells (cDC1s) are leukocytes competent to coordinate antiviral immunity, and thus, the intracellular mechanisms controlling cDC1 function are a matter of intense research. The unfolded protein response (UPR) sensor IRE1 and its associated transcription factor XBP1s control relevant functional aspects in cDC1s including antigen cross-presentation and survival. However, most studies connecting IRE1 and cDC1 function are undertaken in vivo. Thus, the aim of this work is to elucidate whether IRE1 RNase activity can also be modeled in cDC1s differentiated in vitro and reveal the functional consequences of such activation in cells stimulated with viral components. Our data show that cultures of optimally differentiated cDC1s recapitulate several features of IRE1 activation noticed in in vivo counterparts and identify the viral analog Poly(I:C) as a potent UPR inducer in the lineage. In vitro differentiated cDC1s display constitutive IRE1 RNase activity and hyperactivate IRE1 RNase upon genetic deletion of XBP1s, which regulates production of the proinflammatory cytokines IL-12p40, TNF-α and IL-6, Ifna and Ifnb upon Poly(I:C) stimulation. Our results show that a strict regulation of the IRE1/XBP1s axis regulates cDC1 activation to viral agonists, expanding the scope of this UPR branch in potential DC-based therapies.
    Keywords:  IRE1; cDC1s; dendritic cells; proinflammatory cytokines; unfolded protein response
    DOI:  https://doi.org/10.3390/ijms241210205
  3. Contact (Thousand Oaks). 2021 Jan-Dec;4:4 25152564211052392
    Interactome Analysis of the ER Stress Sensor Perk Uncovers Key Components of ER-Mitochondria Contact Sites and Ca2+ Signalling.
    Maria Livia Sassano, Rita Derua, Etienne Waelkens, Patrizia Agostinis, Alexander R van Vliet.
      We recently reported that the ER stress kinase PERK regulates ER-mitochondria appositions and ER- plasma membrane (ER-PM) contact sites, independent of its canonical role in the unfolded protein response. PERK regulation of ER-PM contacts was revealed by a proximity biotinylation (BioID) approach and involved a dynamic PERK-Filamin A interaction supporting the formation of ER-PM contacts by actin-cytoskeleton remodeling in response to depletion of ER-Ca2+ stores. In this report, we further interrogated the PERK BioID interactome by validating through co-IP experiments the interaction between PERK and two proteins involved in Ca2+ handling and ER-mitochondria contact sites. These included the vesicle associated membrane (VAMP)-associated proteins (VAPA/B) and the main ER Ca2+ pump sarcoplasmic/endoplasmic reticulum Ca ATPase 2 (SERCA2). These data identify new putative PERK interacting proteins with a crucial role in membrane contact sites and Ca2+ signaling further supporting the uncanonical role of PERK in Ca2+ signaling through membrane contact sites (MCSs).
    Keywords:  ER stress; cell biology; endoplasmic reticulum; mitochondrial associated membranes (MAM); sarco/endoplasmic reticulum Ca2+-ATPase (SERCA)
    DOI:  https://doi.org/10.1177/25152564211052392
  4. Mol Biol Cell. 2023 Jun 28. mbcE23050205
    The unfolded protein response of the endoplasmic reticulum supports mitochondrial biogenesis by buffering non-imported proteins.
    Katharina Knöringer, Carina Groh, Lena Krämer, Kevin C Stein, Katja G Hansen, Jannik Zimmermann, Bruce Morgan, Johannes M Herrmann, Judith Frydman, Felix Boos.
      Almost all mitochondrial proteins are synthesized in the cytosol and subsequently targeted to mitochondria. The accumulation of non-imported precursor proteins occurring upon mitochondrial dysfunction can challenge cellular protein homeostasis. Here we show that blocking protein translocation into mitochondria results in the accumulation of mitochondrial membrane proteins at the endoplasmic reticulum, thereby triggering the unfolded protein response (UPRER). Moreover, we find that mitochondrial membrane proteins are also routed to the ER under physiological conditions. The level of ER-resident mitochondrial precursors is enhanced by import defects as well as metabolic stimuli that increase the expression of mitochondrial proteins. Under such conditions, the UPRER is crucial to maintain protein homeostasis and cellular fitness. We propose the ER serves as a physiological buffer zone for those mitochondrial precursors that cannot be immediately imported into mitochondria while engaging the UPRER to adjust the ER proteostasis capacity to the extent of precursor accumulation.
    DOI:  https://doi.org/10.1091/mbc.E23-05-0205
  5. Sci Signal. 2023 06 27. 16(791): eabm9454
    The transcription factor XBP1 in dendritic cells promotes the TH2 cell response in airway allergy.
    Gui Yang, Xian-Hai Zeng, Xiao-Rui Geng, Jiang-Qi Liu, Li-Hua Mo, Xiang-Qian Luo, Hua-Zhen Liu, Yuan-Yi Zhang, Li-Teng Yang, Qin-Miao Huang, Xiao-Jun Xiao, Jie Liu, Ling-Zhi Xu, Da-Bo Liu, Xiao-Yu Liu, Zhi-Qiang Liu, Ping-Chang Yang.
      Dendritic cells (DCs) that express T cell immunoglobulin domain molecule-4 (TIM4), a cell surface receptor for phosphatidylserine, induce T helper 2 (TH2) cell responses and allergic reactions. We elucidated the role of the transcription factor X-box-binding protein-1 (XBP1) in the induction of the TH2 cell response through its role in generating TIM4+ DCs. We found that XBP1 was required for TIM4 mRNA and protein expression in airway DCs in response to the cytokine interleukin-2 (IL-2) and that this pathway was required for TIM4 expression on DCs in response to the allergens PM2.5 and Derf1. The IL-2-XBP1-TIM4 axis in DCs contributed to Derf1/PM2.5-induced, aberrant TH2 cell responses in vivo. An interaction between the guanine nucleotide exchange factor Son of sevenless-1 (SOS1) and the GTPase RAS promoted XBP1 and TIM4 production in DCs. Targeting the XBP1-TIM4 pathway in DCs prevented or alleviated experimental airway allergy. Together, these data suggest that XBP1 is required for TH2 cell responses by inducing the development of TIM4+ DCs, which depends on the IL-2-XBP1-SOS1 axis. This signaling pathway provides potential therapeutic targets for the treatment of TH2 cell-dependent inflammation or allergic diseases.
    DOI:  https://doi.org/10.1126/scisignal.abm9454
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