ATF6 and Thrombospondin 4

Abstract

Thrombospondins are secreted, nonstructural, extracellular matrix proteins that are upregulated in the heart and other tissues in response to ischemic injury and pathology. Roles for thrombospondins after they are secreted have been examined in a variety of disease models, including myocardial pathology. However, a recent study published in the journal Cell shifts this paradigm by focusing on roles for intracellular thrombospondins; these authors showed that thrombospondin 4 (Thbs4) can function from within cells to protect the heart by enhancing adaptive aspects of the endoplasmic reticulum stress response that are mediated by activating transcription factor 6 (ATF6). Although this study was performed in the cardiac context, the results add to our understanding of protein folding and quality control in all tissues. Moreover, the findings underscore the potential widespread therapeutic benefit of enhancing adaptive responses that are regulated by ATF6. The study by Lynch et al,1 which was performed in the laboratory of Dr Jeffery Molkentin, used a series of molecular approaches, including in vivo gain-of-function and loss-of-function models in mice, to demonstrate new roles for Thbs4 in the management of endoplasmic reticulum (ER) protein quality control in the heart. The ER is the site of synthesis and folding of most secreted and membrane proteins, which constitute at least 35% of all proteins.2 Secreted and membrane proteins are synthesized by ER-bound ribosomes, cotranslationally translocated across the ER membrane, and folded in the lumen of the ER, after which they are transported to the Golgi, where they are sorted to their final destinations.3,4 The ER lumen is populated with chaperones, protein disulfide isomerases, protein oxidoreductases, and other proteins that are responsible for the proper protein folding. This elaborate machinery requires an optimal ER environment for efficient protein folding. Conditions such as myocardial ischemia, hypertrophy, and heart failure alter …