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Synthetic embryonic lethality upon deletion of the ER cochaperone p58(IPK) and the ER stress sensor ATF6?.

ABSTRACT: The unfolded protein response (UPR) is activated as a consequence of alterations to ER homeostasis. It upregulates a group of ER chaperones and cochaperones, as well as other genes that improve protein processing within the secretory pathway. The UPR effector ATF6? augments-but is not essential for-maximal induction of ER chaperones during stress, yet its role, if any, in protecting cellular function during normal development and physiology is unknown. A systematic analysis of multiple tissues from Atf6?-/- mice revealed that all tissues examined were grossly insensitive to loss of ATF6?. However, combined deletion of ATF6? and the ER cochaperone p58(IPK) resulted in synthetic embryonic lethality. These findings reveal for the first time that an intact UPR can compensate for the genetic impairment of protein folding in the ER in vivo. The also expose a role for p58(IPK) in normal embryonic development.

SUBMITTER: Gomez JA

PROVIDER: S-EPMC3901050 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Synthetic embryonic lethality upon deletion of the ER cochaperone p58(IPK) and the ER stress sensor ATF6α.

Gomez Javier A JA Tyra Heather M HM DeZwaan-McCabe Diane D Olivier Alicia K AK Rutkowski D Thomas DT

Biochemical and biophysical research communications 20131122 1

The unfolded protein response (UPR) is activated as a consequence of alterations to ER homeostasis. It upregulates a group of ER chaperones and cochaperones, as well as other genes that improve protein processing within the secretory pathway. The UPR effector ATF6α augments-but is not essential for-maximal induction of ER chaperones during stress, yet its role, if any, in protecting cellular function during normal development and physiology is unknown. A systematic analysis of multiple tissues f ...[more]

PMID: 24275136

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Project description:ObjectiveProtein kinase-like endoplasmic reticulum kinase (PERK) and protein kinase R (PKR) are implicated in endoplasmic reticulum stress-induced arthritis and pro-inflammatory cytokine-mediated cartilage degradation in vitro, respectively. We determined whether knockout of the cellular inhibitor of PERK and PKR, P58(IPK) causes joint degeneration in vivo and whether these molecules are activated in human osteoarthritis (OA).Materials and methodsSections of knee joints from P58(IPK)-null and wild-type mice aged 12-13 and 23-25 months were stained with toluidine blue and scored for degeneration using the osteoarthritis research society international (OARSI) system. Bone changes were assessed by radiology and high-resolution micro-computed tomography of hind limbs. Sections from the medial tibial plateaus of two human knees, removed in total knee replacement surgery for OA, were immunolabelled for phosphorylated PERK and PKR and P58(IPK).ResultsKnockout mice exhibited narrower tibiae (p = 0.0031) and smaller epiphyses in tibiae (p = 0.0004) and femora (p = 0.0214). Older knockout mice had reduced total volume inside the femoral periosteal envelope (p = 0.023), reduced tibial (p = 0.03), and femoral (p = 0.0012) bone volumes (BV) and reduced femoral BV fraction (p = 0.025). Compared with wild-types, younger P58(IPK)-null mice had increased OARSI scores in medial femoral condyles (p = 0.035). Thirty four percent of null mice displayed severe joint degeneration with complete articular cartilage loss from the medial compartment and heterotopic chondro-osseous tissue in the medial joint capsule. Phosphorylated PERK and PKR were localized throughout human osteoarthritic tibial plateaus but, in particular, in areas exhibiting the most degeneration. There was limited expression of P58(IPK).ConclusionThis study is the first to reveal a critical role for P58(IPK) in maintaining joint integrity in vivo, implicating the PKR and PERK stress signaling pathways in bony changes underlying the pathogenesis of joint degeneration.

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Synthetic embryonic lethality upon deletion of the ER cochaperone p58(IPK) and the ER stress sensor ATF6?.

Publications

Synthetic embryonic lethality upon deletion of the ER cochaperone p58(IPK) and the ER stress sensor ATF6α.

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