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  • br Acknowledgments br Multicellular organisms respond rapidl

    2021-03-26


    Acknowledgments
    Multicellular organisms respond rapidly, and adapt to cellular stress to maximize cell survival. The cellular stress response, also called (ISR), is universally conserved and independent of the stressor. ISR induces rapid, transient reprogramming of cellular protein translation to decrease growth-related and increase stress-related proteins. ISR also changes cellular response to subsequent stress that affects the long-term adaptation of the cell to chronic stress. Cell stress response is initiated by 1 of 4 stress-sensing kinases, all of which phosphorylate the alpha subunit of the eukaryotic translation initiation factor 2 (EIF2A). This converts EIF2A from a substrate to an inhibitor of its own guanine nucleotide exchange factor EIF2B, leading to a decrease in global protein synthesis. ISR is terminated by dephosphorylation of EIF2A by a protein phosphatase PP1, which requires the direct association of its regulatory subunits protein phosphatase 1 regulatory subunit 15A and 15B (PPP1R15A and PPP1R15B) with globular (G) actin. Paradoxically, phosphorylation of EIF2A also favors the translation of the activating transcription factor 4 (ATF4), which activates the pro-survival effects of autophagy in the short term, but prolonged activation of ATF4 activates the DNA-damage inducible transcript 3 protein (DDIT3) to induce cell death. Depending on the severity and duration of stress, the final outcome of cellular stress, therefore, can be cell survival or cell death. Additionally, the cell must elect to promote apoptosis or immunogenic cell death. The control switch that modulates cell stress response between cell survival and cell death is key to multiple diseases because excessive cell death is linked to inflammation. Actin is a major component of cellular homeostatic functions and an early target of cell stress response., EIF2A signaling regulates the Mometasone furoate cytoskeleton such as by the direct binding of the stress sensing kinase eukaryotic translation initiation factor 2 alpha kinase 2 (EIF2AK2) with gelsolin, which inhibit gelsolin’s actin-severing function. Actin is also a major component of the protein translational machinery. G-actin binds the regulatory subunits of PP1 to dephosphorylate pEIF2A, which restores cellular homeostasis. Downstream of EIF2A, DDIT3-induced cell death is also regulated by actin-binding proteins, including the villin-1/gelsolin homolog advillin., The pEIF2A pathway is activated upon infection with most Crohn’s disease (CD)-associated pathogens. Marked decrease in autophagy and increased susceptibility to ileal bacterial infection is also observed in mice with intestinal epithelial cell (IEC)-specific expression of non-phosphorylatable EIF2A. Similarly, in patients with CD, pEIF2A is increased in mucosal tissue with active disease. Ablation of cell death pathways following pEIF2A signaling alleviates colitis in mice. Despite this, the pathophysiological relevance of EIF2A signaling in CD is unknown. Immunity-related GTPase family M protein (IRGM) plays a role in innate immunity by regulating autophagy in response to several intracellular pathogens. IRGM has been identified in genome wide association studies and meta-analysis as a genetic risk factor in CD. IRGM polymorphism confers susceptibility to CD but not ulcerative colitis and is associated with more frequent need for surgery. EIF2A signaling is essential for stress-induced autophagy gene expression including ATG16L1, another autophagy gene linked to the pathogenesis of CD. Even though IRGM is the strongest autophagy gene linked to CD, its regulation by EIF2A signaling remains unknown. Overexpression of IRGM in CD suggests that its role in CD pathogenesis is independent of its effect on xenophagy, but its link to intestinal inflammation has not been identified. Increased cell death by RIPK1-RIPK3 (receptor interacting serine/threonine kinase 1, 3) mediated necroptosis and the release of damage associated molecular patterns (DAMPs) such as HMGB1 (high mobility group box 1) are associated with intestinal inflammation and pathogenesis of CD but the molecular basis for their activation is unknown., Cellular stress can induce necroptosis and release of DAMPs, but the role of EIF2A signaling in CD-associated necroptosis and HMGB1 release has Mometasone furoate not been determined. In view of that, it is clear that discovering the detailed mechanisms of IEC stress response could improve assessment and treatment of CD patients.