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A thrombospondin-dependent pathway for a protective ER stress response.
Thrombospondin (Thbs) proteins are induced in sites of tissue damage or active remodeling. The endoplasmic reticulum (ER) stress response is also prominently induced with disease where it regulates protein production and resolution of misfolded proteins. Here we describe a function for Thbs as ER-resident effectors of an adaptive ER stress response. Thbs4 cardiac-specific transgenic mice were protected from myocardial injury, whereas Thbs4(-/-) mice were sensitized to cardiac maladaptation. Thbs induction produced a unique profile of adaptive ER stress response factors and expansion of the ER and downstream vesicles. Thbs bind the ER lumenal domain of activating transcription factor 6α (Atf6α) to promote its nuclear shuttling. Thbs4(-/-) mice showed blunted activation of Atf6α and other ER stress-response factors with injury, and Thbs4-mediated protection was lost upon Atf6α deletion. Hence, Thbs can function inside the cell during disease remodeling to augment ER function and protect through a mechanism involving regulation of Atf6α.
Authors : Lynch Jeffrey M , Maillet Marjorie , Vanhoutte Davy , Schloemer Aryn , Sargent Michelle A , Blair N Scott , Lynch Kaari A , Okada Tetsuya , Aronow Bruce J , Osinska Hanna , Prywes Ron , Lorenz John N , Mori Kazutoshi , Lawler Jack , Robbins Jeffrey , Molkentin Jeffery D ,
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Pathways :
WP1019: FAS pathway and Stress induction of HSP regulation
WP1040: Inflammatory Response Pathway
WP1138: FAS pathway and Stress induction of HSP regulation
WP1156: Inflammatory Response Pathway
WP1493: Carbon assimilation C4 pathway
WP1527: stress response
WP2344: vitamin B6 (pyridoxine, pyridoxal, pyridoxamine) biosynthesis and salvage pathway
WP314: FAS pathway and Stress induction of HSP regulation
WP40: Inflammatory Response Pathway
WP453: Inflammatory Response Pathway
WP458: Inflammatory Response Pathway
WP511: FAS pathway and Stress induction of HSP regulation
WP571: FAS pathway and Stress induction of HSP regulation
WP710: DNA damage response (only ATM dependent)
WP788: FAS pathway and Stress induction of HSP regulation
WP89: FAS pathway and Stress induction of HSP regulation
WP902: FAS pathway and Stress induction of HSP regulation
WP920: Inflammatory Response Pathway
WP1: Statin Pathway
WP10: IL-9 Signaling Pathway
WP1004: Kit Receptor Signaling Pathway
WP1010: Wnt Signaling Pathway and Pluripotency
WP1011: T Cell Receptor Signaling Pathway
WP1012: IL-7 Signaling Pathway
WP1014: Androgen receptor signaling pathway
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Bibliography :
[22682248] A thrombospondin-dependent pathway for a protective ER stress response.
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