Abstract
Mutations in TGF-β–activated kinase 1 binding protein 2 (TAB2) have been implicated in the pathogenesis of dilated cardiomyopathy and/or congenital heart disease in humans, but the underlying mechanisms are currently unknown. Here, we identified an indispensable role for TAB2 in regulating myocardial homeostasis and remodeling by suppressing receptor-interacting protein kinase 1 (RIPK1) activation and RIPK1-dependent apoptosis and necroptosis. Cardiomyocyte-specific deletion of Tab2 in mice triggered dilated cardiomyopathy with massive apoptotic and necroptotic cell death. Moreover, Tab2-deficient mice were also predisposed to myocardial injury and adverse remodeling after pathological stress. In cardiomyocytes, deletion of TAB2 but not its close homolog TAB3 promoted TNF-α–induced apoptosis and necroptosis, which was rescued by forced activation of TAK1 or inhibition of RIPK1 kinase activity. Mechanistically, TAB2 critically mediates RIPK1 phosphorylation at Ser321 via a TAK1-dependent mechanism, which prevents RIPK1 kinase activation and the formation of RIPK1-FADD-caspase-8 apoptotic complex or RIPK1-RIPK3 necroptotic complex. Strikingly, genetic inactivation of RIPK1 with Ripk1-K45A knockin effectively rescued cardiac remodeling and dysfunction in Tab2-deficient mice. Together, these data demonstrated that TAB2 is a key regulator of myocardial homeostasis and remodeling by suppressing RIPK1-dependent apoptosis and necroptosis. Our results also suggest that targeting RIPK1-mediated cell death signaling may represent a promising therapeutic strategy for TAB2 deficiency–induced dilated cardiomyopathy.
Highlights
Loss of cardiomyocytes by apoptotic and necrotic death is a crucial event underlying pathological cardiac remodeling and heart failure [1,2]
This study identified an essential role for TAB2 in myocardial survival and homeostasis by suppressing RIPK1 kinase activation and RIPK1-dependent apoptosis and necroptosis
We showed that acute deletion of TAB2 in the adult heart led to dilated cardiomyopathy through the induction of apoptotic and necroptotic cell death, recapitulating the cardiac phenotype in patients with TAB2 mutations [29,30,31,32,33,34,35]
Summary
Loss of cardiomyocytes by apoptotic and necrotic death is a crucial event underlying pathological cardiac remodeling and heart failure [1,2]. Ligation of TNFR1 triggers the assembly of a plasma membrane bound signaling complex, termed complex I, consisting of TNF receptor-associated protein with death domain (TRADD), TNF receptor-associated protein 2 (TRAF2), cellular inhibitor of apoptosis protein 1 and 2 (cIAP1 and cIAP2), and RIPK1 [10]. Under apoptosis-inducing conditions such as inhibition of NFkB, the TNFR1 complex internalizes and converts to a cell death-inducing complex, termed complex II, consisting of TRADD, Fasassociated protein with death domain (FADD), and caspase-8 [10]. Recent studies identified another cell death checkpoint, which is controlled by RIPK1 kinase activity. The molecular signaling events that control RIPK1 kinase-dependent cell death checkpoint remain elusive
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