A Thrombospondin-Dependent Pathway for?a Protective ER Stress Response

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• 作者：Jeffrey  ; M. Lynch¹ ; Marjorie Maillet¹ ; Davy Vanhoutte¹ ; Aryn Schloemer¹ ; Michelle  ; A. Sargent¹ ; ² ; N.  ; Scott Blair¹ ; Kaari  ; A. Lynch³ ; Tetsuya Okada⁴ ; Bruce  ; J. Aronow¹ ; Hanna Osinska¹ ; Ron Prywes⁵ ; John  ; N. Lorenz⁶ ; Kazutoshi Mori⁴ ; Jack Lawler⁷ ; Jeffrey Robbins¹ ; Jeffery  ; D. Molkentin¹ ; ² ; ^{jeff.molkentin@cchmc.org}
• 刊名：Cell
• 出版年：2012
• 出版时间：8 June, 2012
• 年：2012
• 卷：149
• 期：6
• 页码：1257-1268
• 全文大小：2050 K

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ass=""h3"">Summary

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^??/sup> 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 6¦Á (Atf6¦Á) to promote its nuclear shuttling. Thbs4^??/sup> mice showed blunted activation of Atf6¦Á and other ER stress-response factors with injury, and Thbs4-mediated protection was lost upon Atf6¦Á deletion. Hence, Thbs can function inside the cell during disease remodeling to augment ER function and protect through a mechanism involving regulation of Atf6¦Á.