Abstract
Objective: Necroptosis is a new caspase-independent, regulated form of necrosis, which has recently been implicated in ischemic cardiac injury and remodeling. This study aims to determine a novel ubiquitination-dependent mechanism that regulates necroptosis in the heart and the implications of necroptosis signaling in the setting of ischemic injury and remodeling. Methods and Results: Here we identified a novel ubiquitination-dependent mechanism mediated by the E3 ubiquitin ligase TRAF2 (TNF receptor associated factor-2) and the deubiquitinase CYLD (cylindromatosis), which critically regulates myocardial necroptosis and pathological remodeling. TRAF2 and CYLD specifically regulate K63-linked protein ubiquitination, which regulates signal transduction but not proteasomal degradation. Intriguingly, CYLD is up-regulated, but TRAF2 is down-regulated, in the heart after ischemia-reperfusion injury. We found that wild-type TRAF2 inhibits, whereas the ligase inactive mutant TRAF2-ΔRING promotes cardiomyocyte necroptosis. Importantly, acute deletion of TRAF2 in the adult heart in Traf2 fl/fl -MerCreMer mice induces severe dilated cardiomyopathy and lethal heart failure by promoting myocardial necroptosis. Conversely, AAV9-mediated TRAF2 gene transfer significantly attenuates ischemic-reperfusion injury. On the other hand, CYLD overexpression promotes, whereas CYLD deletion inhibits cardiomyocyte necroptosis. In vivo , genetic ablation of CYLD in Cyld-/- mice attenuates ischemic myocardial injury and adverse remodeling by suppressing myocardial necroptosis. Mechanistically, TRAF2 and CYLD opposingly regulate K63-linked polyubiquitination of TAK1 (TGFβ-activated kinase 1), TAK1-RIP1 interaction, and the formation of RIP1-RIP3 necrosome. These results thus identify a ubiquitination-dependent mechanism of necroptosis mediated by TRAF2 and CYLD, providing a new paradigm of necroptosis signaling. Conclusion: The E3 ligase TRAF2 and the deubiquitinase CYLD, as a suppressor and an activator of necroptosis respectively, opposingly regulate myocardial homeostasis, ischemic injury, and remodeling, thus representing promising therapeutic targets for heart disease.
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