Modulation of poly(ADP-Ribose) polymerase-1 (PARP-1)-mediated oxidative cell injury by ring finger protein 146 (RNF146) in cardiac myocytes

Domokos Gerö, Petra Szoleczky, Athanasia Chatzianastasiou, Andreas Papapetropoulos, Csaba Szabo

    Research output: Contribution to journalArticle

    20 Scopus citations

    Abstract

    Poly(ADP-ribose) polymerase-1 (PARP-1) activation is a hallmark of oxidative stress–induced cellular injury that can lead to energetic failure and necrotic cell death via depleting the cellular nicotinamide adenine dinucleotide (NAD+) and ATP pools. Pharmacological PARP-1 inhibition or genetic PARP-1 deficiency exert protective effects in multiple models of cardiomyocyte injury. However, the connection between nuclear PARP-1 activation and depletion of the cytoplasmic and mitochondrial energy pools is poorly understood. By using cultured rat cardiomyocytes, here we report that ring finger protein 146 (RNF146), a cytoplasmic E3-ubiquitin ligase, acts as a direct interactor of PARP-1. Overexpression of RNF146 exerts protection against oxidant-induced cell death, whereas PARP-1–mediated cellular injury is augmented after RNF146 silencing. RNF146 translocates to the nucleus upon PARP-1 activation, triggering the exit of PARP-1 from the nucleus, followed by rapid degradation of both proteins. PARP-1 and RNF146 degradation occurs in the early phase of myocardial ischemia-reperfusion injury; it precedes the induction of heat shock protein expression. Taken together, PARP-1 release from the nucleus and its rapid degradation represent newly identified steps of the necrotic cell death program induced by oxidative stress. These steps are controlled by the ubiquitin-proteasome pathway protein RNF146. The current results shed new light on the mechanism of necrotic cell death. RNF146 may represent a distinct target for experimental therapeutic intervention of oxidant-mediated cardiac injury.

    Original languageEnglish (US)
    Pages (from-to)313-328
    Number of pages16
    JournalMolecular Medicine
    Volume20
    Issue number1
    DOIs
    StatePublished - Jan 1 2014

    ASJC Scopus subject areas

    • Molecular Medicine
    • Molecular Biology
    • Genetics
    • Genetics(clinical)

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