A Thrombospondin-Dependent Pathway for a Protective ER Stress Response

Abstract

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 novel function for Thbs’ as ER resident effectors of an adaptive ER stress response. Thbs4 cardiac-specific transgenic mice were protected from myocardial injury while 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. The type-3 repeat domain in Thbs’ bind the ER luminal domain of activating transcription factor 6α (Atf6α) to promote its nuclear shuttling. Thbs4−/−mice failed to show activation of Atf6α and other ER stress response factors with injury, and Thbs4-mediated protection was lost when Atf6α was deleted. Hence, Thbs’ can function inside the cell during disease/remodeling to augment ER function and protect through a mechanism involving regulation of Atf6α.

Translational Profiles of Medullary Myofibroblasts during Kidney Fibrosis

“…Similarly, Thrombospondin-4 (Thbs4) is an extracellular matrix glycoprotein now recognized to induce the endoplasmic reticulum stress response after cardiac injury. 23 Knockout mice are more susceptible to fibrosis and transgenic mice are protected from fibrosis, so by extension Thbs4 upregulation in kidney myofibroblasts may also reflect an adaptive, antifibrotic endoplasmic reticulum stress response to injury. The top 25 myofibroblast-specific upregulated or downregulated genes are presented in Tables 1 and 2.…”

COMP-assisted collagen secretion - a novel intracellular function required for fibrosis

“…Expression of thrombospondin-1 (TSP-1) in COMP-deficient cells, which has also been implicated in impacting collagen expression as well as fibril organization (Sweetwyne et al, 2010;Sweetwyne and Murphy-Ullrich, 2012) did not differ from controls. Interestingly, the other pentameric thrombospondin, thrombospondin-4 (TSP-4), which is also stimulated by mechanical load (Cingolani et al, 2011), implicated in cardiac fibrosis (Frolova et al, 2012) and in an adaptive endoplasmic reticulum (ER) stress response (Lynch et al, 2012) might be a candidate for functional compensation because its expression was significantly up-regulated in COMP-deficient fibroblasts.…”

Endoplasmic reticulum stress: a novel mechanism and therapeutic target for cardiovascular diseases

“…In order to clear the accumulated proteins, many chaperone genes are induced at the transcriptional level and activate the ER-associated degradation (ERAD) system, which can translocate and remove misfolded proteins through proteasomal degradation. These processes are identified as the unfolded protein response (UPR) [10,11] . However, if unresolved, ERS is lethal to cells via what is recognized as ERSinduced apoptosis [12] .…”