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Abstract 468: TAB2 is Molecular Switch That Critically Regulates Myocardial Survival and Necroptosis


 Our recent study identified a key role for TAK1 (transforming growth factor β activated kinase-1) in regulating myocardial remodeling and heart failure propensity by antagonizing necroptosis, also termed programmed necrosis (
 Circulation
 2014;130:2162-2172). TAB2 (TAK1 binding protein-2) is an adaptor protein that regulates TAK1 activation and downstream signaling. Here we tested the hypothesis that TAB2 functions as a critical regulator of myocardial necroptosis and pathological remodeling. We found that both TAB2 and TAK1 were up-regulated during compensatory cardiac hypertrophy but down-regulated in end-stage heart failure. Genetic ablation of TAB2 in cardiomyocytes, but not other TAK1 binding proteins TAB1 or TAB2, markedly increased necroptosis in response to TNFα stimulation. Genetic deletion of RIP3 (receptor interacting protein-3), a key regulator of necroptosis, also largely blocked cell death in TAB2-deficent cells, further confirming the role of TAB2 in regulating necroptotic cell death. Mechanistically, our data showed that TAB2 functions as a molecular switch that tightly regulates TAK1-RIP1 interaction (pro-survival) and the RIP1-RIP3 necrosome formation (pro-necroptosis). We further showed that loss of TAB2 promotes necroptosis in cardiomyocytes via two independent mechanisms: acutely through the induction of RIP1-RIP3 necrosome and later through inhibition of the NFκB pathway. Importantly, cardiac-specific ablation of TAB2 in mice showed enhanced pathological remodeling with massive fibrosis and necroptosis, and the TAB2-deficient mice gradually developed dilated cardiomyopathy and heart failure starting 2 months old. Moreover, the TAB2-deficient mice are also predisposed to heart failure after pathological stress by pressure overload or myocardial infarction, suggesting a protective role of TAB2 in cardiac stress response. These results strongly indicate that TAB2 functions as a molecular switch that critically regulates the pro-survival TAK1 signaling and the necroptosis machinery, thus playing a critical role in myocardial survival and stress response. The TAB2-TAK1 signaling network may serve as a novel therapeutic target in heart disease and other pathological conditions driven by necroptosis.
