ATF6 [corrected] and thrombospondin 4: the dynamic duo of the adaptive endoplasmic reticulum stress response

Abstract

Thrombospondins are secreted, extracellular matrix (ECM) proteins that are upregulated in the heart and other tissues in response to ischemic injury and myocardial stress. 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 by Lynch et al 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 (ER) stress response that are mediated by activating transcription factor 6, ATF6. Although this study was carried out 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.

Figure. Roles of GRP78 and Thrombospondin-4 in ATF6 Activation

The ER-transmembrane proteins, IRE-1, PERK, and ATF6, are sensors of protein folding in the ER. When ER protein folding is optimal, the ER luminal domains of each sensor are associated with the ER chaperone, GRP78 (A). GRP78 is an ER resident protein by virtue of its C-terminal KDEL sequence, which facilitates its retrieval from the Golgi to the ER via its binding to the KDEL receptor. Because it binds to GRP78, ATF6 is anchored in the ER, which keeps ATF6 from being activated. However, when ER protein folding is impaired, for example, during ER stress (red arrows), GRP78 relocates to misfolded proteins as they accumulate (B); since, under these conditions, GRP78 is no longer bound to ATF6 in the ER, ATF6 is free to relocate to the Golgi (C). In the Golgi, ATF6 is cleaved by S1P and S2P (D) to form an active transcription factor that induces ER stress response genes (E), including ATF6 and GRP78, which primarily mediate pleiotropic adaptive, or protective responses (F). Thrombospondin-4 (Thbs4) is synthesized as monomers in the ER, which assemble into pentamers (G) that transit from the ER lumen to the Golgi (H), then to secretory vesicles, from which Thbs4 is eventually secreted (I). Extracellular Thbs4 binds to structural ECM proteins and modulates the ECM in response to tissue damage, providing cardioprotective and adaptive ECM remodeling (J). The study by Lynch et al showed that Thbs4 can bind to ATF6 (K) and facilitate its activation, most likely by facilitating its translocation to the Golgi (L). Since Thbs4 is retained in the ER during some ER stress treatments that are known to stimulate ATF6 translocation to the Golgi (see text), it may be that there are some conditions under which ATF6 relocation from the ER to the Golgi, and thus, ATF6 activation can take place in a Thbs4-independent manner (C and D).