Cullin Deneddylation Suppresses the Necroptotic Pathway in Cardiomyocytes

Abstract

Cardiomyocyte death in the form of apoptosis and necrosis represents a major cellular mechanism underlying cardiac pathogenesis. Recent advances in cell death research reveal that not all necrosis is accidental, but rather there are multiple forms of necrosis that are regulated. Necroptosis, the earliest identified regulated necrosis, is perhaps the most studied thus far, and potential links between necroptosis and Cullin-RING ligases (CRLs), the largest family of ubiquitin E3 ligases, have been postulated. Cullin neddylation activates the catalytic dynamic of CRLs; the reverse process, Cullin deneddylation, is performed by the COP9 signalosome holocomplex (CSN) that is formed by eight unique protein subunits, COPS1/CNS1 through COPS8/CNS8. As revealed by cardiomyocyte-restricted knockout of Cops8 (Cops8-cko) in mice, perturbation of Cullin deneddylation in cardiomyocytes impairs not only the functioning of the ubiquitin–proteasome system (UPS) but also the autophagic–lysosomal pathway (ALP). Similar cardiac abnormalities are also observed in Cops6-cko mice; and importantly, loss of the desmosome targeting of COPS6 is recently implicated as a pathogenic factor in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). Cops8-cko causes massive cardiomyocyte death in the form of necrosis rather than apoptosis and rapidly leads to a progressive dilated cardiomyopathy phenotype as well as drastically shortened lifespan in mice. Even a moderate downregulation of Cullin deneddylation as seen in mice with Cops8 hypomorphism exacerbates cardiac proteotoxicity induced by overexpression of misfolded proteins. More recently, it was further demonstrated that cardiomyocyte necrosis caused by Cops8-cko belongs to necroptosis and is mediated by the RIPK1–RIPK3 pathway. This article reviews these recent advances and discusses the potential links between Cullin deneddylation and the necroptotic pathways in hopes of identifying potentially new therapeutic targets for the prevention of cardiomyocyte death.

Catecholamine Surges Cause Cardiomyocyte Necroptosis via a RIPK1–RIPK3-Dependent Pathway in Mice

“…However, more recent studies suggest that the RIPK3–MLKL axis may still be important for myocardial necroptosis in I/R injury ( 34 ). Moreover, the canonical RIPK1–RIPK3–MLKL pathway has been implicated in cardiomyocyte necroptosis induced by genetic interrogations of key cellular processes in mice; the perturbation of Cullin deneddylation by cardiomyocyte-restricted ablation of Cops8 gene and the suppression of nuclear DNA-encoded mitochondrial genes required for ATP synthesis due to the knockout of the Hippo signaling effector TEAD1 are among the examples ( 41 , 60 , 61 ). It is well-known that induction of necroptosis by the activation of TNFR1 requires RIPK1 kinase activity ( 26 ).…”

The KEAP1-NRF2 pathway: Targets for therapy and role in cancer

“…D) Small molecule inhibitors, ETGE motif containing peptides and PROTACs can disrupt the interaction between NRF2 and KEAP1, and lead to NRF2 activation [ 36 ]. E) Inhibition of NEDD8-activating enzymes NAE1 or DCN1 by small molecule inhibitors or by increasing deneddylation by CSN, results in the activation of NRF2 [ 37 , 38 , 39 ]. Activated NRF2 accumulates in the nucleus and interacts with other TFs and cofactors to regulate the transcription of its target genes, encoding various proteins involved e.g., in xenobiotic detoxification, antioxidant pathways, inflammatory and metabolic processes, as well as regulation of cell autophagy and cell death.…”