Abstract
Thrombospondins (Thbs) are a family of five secreted matricellular glycoproteins in vertebrates that broadly affect cell-matrix interaction. While Thbs4 is known to protect striated muscle from disease by enhancing sarcolemmal stability through increased integrin and dystroglycan attachment complexes, here we show that Thbs3 antithetically promotes sarcolemmal destabilization by reducing integrin function, augmenting disease-induced decompensation. Deletion of Thbs3 in mice enhances integrin membrane expression and membrane stability, protecting the heart from disease stimuli. Transgene-mediated overexpression of α7β1D integrin in the heart ameliorates the disease predisposing effects of Thbs3 by augmenting sarcolemmal stability. Mechanistically, we show that mutating Thbs3 to contain the conserved RGD integrin binding domain normally found in Thbs4 and Thbs5 now rescues the defective expression of integrins on the sarcolemma. Thus, Thbs proteins mediate the intracellular processing of integrin plasma membrane attachment complexes to regulate the dynamics of cellular remodeling and membrane stability.
Highlights
Thrombospondins (Thbs) are a family of five secreted matricellular glycoproteins in vertebrates that broadly affect cell-matrix interaction
Thbs[3] was mildly but significantly induced in the hearts of Csrp3−/− mice[26], a model of dilated cardiomyopathy (Fig. 1a and Supplementary Fig 1a). Cardiac pathology in these select mouse models was associated with endoplasmic reticulum (ER) stress and binding immunoglobulin protein (BiP) and activating transcription factor 6α (ATF6α) protein induction (Supplementary Fig. 1a)
Immunohistochemical analysis of heart sections from CnA transgenic mice and mice subjected to transverse aortic constriction (TAC) showed cardiomyocyte restricted, intracellular localization of Thbs[3] protein with cytoplasmic desmin staining, which was directly coincident with the ER chaperone protein disulfide isomerase (PDI) (Fig. 1b, c)
Summary
Thrombospondins (Thbs) are a family of five secreted matricellular glycoproteins in vertebrates that broadly affect cell-matrix interaction. The ER-stress response involves activation of 3 distinct branches consisting of PKR-like ER kinase, inositol requiring enzyme 1α (Ire1α) and activating transcription factor 6α (ATF6α)[23]. During their maturation in the secretory pathway, Thbs proteins interact with ER resident effectors such as BiP and ATF6α24, resulting in the induction of an adaptive stress response, vesicular expansion, and reduced protein aggregation with augmented protein secretion[19,21,24]. Overexpression of Thbs[4] dramatically enhanced sarcolemmal stability that rescued mouse models of muscular dystrophy through a mechanism involving enhanced integrin and dystroglycan-sarcoglycan attachment complexes in the plasma membrane[21]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
