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Role of Endoplasmic Reticulum Stress Sensor IRE1? in Cellular Physiology, Calcium, ROS Signaling, and Metaflammation.

ABSTRACT: Inositol-requiring transmembrane kinase endoribonuclease-1? (IRE1?) is the most prominent and evolutionarily conserved unfolded protein response (UPR) signal transducer during endoplasmic reticulum functional upset (ER stress). A IRE1? signal pathway arbitrates yin and yang of cellular fate in objectionable conditions. It plays several roles in fundamental cellular physiology as well as in several pathological conditions such as diabetes, obesity, inflammation, cancer, neurodegeneration, and in many other diseases. Thus, further understanding of its molecular structure and mechanism of action during different cell insults helps in designing and developing better therapeutic strategies for the above-mentioned chronic diseases. In this review, recent insights into structure and mechanism of activation of IRE1? along with its complex regulating network were discussed in relation to their basic cellular physiological function. Addressing different binding partners that can modulate IRE1? function, UPRosome triggers different downstream pathways depending on the cellular backdrop. Furthermore, IRE1? are in normal cell activities outside the dominion of ER stress and activities under the weather of inflammation, diabetes, and obesity-related metaflammation. Thus, IRE1 as an ER stress sensor needs to be understood from a wider perspective for comprehensive functional meaning, which facilitates us with assembling future needs and therapeutic benefits.

SUBMITTER: Riaz TA

PROVIDER: S-EPMC7290600 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Role of Endoplasmic Reticulum Stress Sensor IRE1α in Cellular Physiology, Calcium, ROS Signaling, and Metaflammation.

Riaz Thoufiqul Alam TA Junjappa Raghu Patil RP Handigund Mallikarjun M Ferdous Jannatul J Kim Hyung-Ryong HR Chae Han-Jung HJ

Cells 20200508 5

Inositol-requiring transmembrane kinase endoribonuclease-1α (IRE1α) is the most prominent and evolutionarily conserved unfolded protein response (UPR) signal transducer during endoplasmic reticulum functional upset (ER stress). A IRE1α signal pathway arbitrates yin and yang of cellular fate in objectionable conditions. It plays several roles in fundamental cellular physiology as well as in several pathological conditions such as diabetes, obesity, inflammation, cancer, neurodegeneration, and in ...[more]

PMID: 32397116

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Project description:The unfolded-protein response (UPR) is a signal transduction cascade triggered by perturbation of the homeostasis of the endoplasmic reticulum (ER). UPR resolves ER stress by activating a cascade of cellular responses, including the induction of molecular chaperones, translational attenuation, ER-associated degradation, and other mechanisms. Under prolonged and irremediable ER stress, however, the UPR can also trigger apoptosis. Here, we report that in cells infected with the avian coronavirus infectious bronchitis virus (IBV), ER stress was induced and the IRE1?-XBP1 pathway of UPR was activated. Knockdown and overexpression experiments demonstrated that IRE1? protects infected cells from IBV-induced apoptosis, which required both its kinase and RNase activities. Our data also suggest that splicing of XBP1 mRNA by IRE1? appears to convert XBP1 from a proapoptotic XBP1u protein to a prosurvival XBP1s protein. Moreover, IRE1? antagonized IBV-induced apoptosis by modulating the phosphorylation status of the proapoptotic c-Jun N-terminal kinase (JNK) and the prosurvival RAC-alpha serine/threonine-protein kinase (Akt). Taken together, the data indicate that the ER stress sensor IRE1? is activated in IBV-infected cells and serves as a survival factor during coronavirus infection.Animal coronaviruses are important veterinary viruses, which could cross the species barrier, becoming severe human pathogens. Molecular characterization of the interactions between coronaviruses and host cells is pivotal to understanding the pathogenicity and species specificity of coronavirus infection. It has been well established that the endoplasmic reticulum (ER) is closely associated with coronavirus replication. Here, we report that inositol-requiring protein 1 alpha (IRE1?), a key sensor of ER stress, is activated in cells infected with the avian coronavirus infectious bronchitis virus (IBV). Moreover, IRE1? is shown to protect the infected cells from apoptosis by modulating the unfolded-protein response (UPR) and two kinases related to cell survival. This study demonstrates that UPR activation constitutes a major aspect of coronavirus-host interactions. Manipulations of the coronavirus-induced UPR may provide novel therapeutic targets for the control of coronavirus infection and pathogenesis.

Dataset Information

Role of Endoplasmic Reticulum Stress Sensor IRE1? in Cellular Physiology, Calcium, ROS Signaling, and Metaflammation.

Publications

Role of Endoplasmic Reticulum Stress Sensor IRE1α in Cellular Physiology, Calcium, ROS Signaling, and Metaflammation.

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