Modulation of poly(ADP-ribose) polymerase-1 (PARP-1)-mediated oxidative cell injury by ring finger protein 146 (RNF146) in cardiac myocytes.
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.
Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, United States of America.
Domokos
D
Gerö
Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, United States of America.
Petra
P
Szoleczky
Faculty of Pharmacy, University of Athens, Athens, Greece.
Athanasia
A
Chatzianastasiou
Faculty of Pharmacy, University of Athens, Athens, Greece.
Andreas
A
Papapetropoulos
Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, United States of America.
Csaba
C
Szabo
D000818:Animals; D016923:Cell Death; D002460:Cell Line; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D015428:Myocardial Reperfusion Injury / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
D012333:RNA, Messenger; C000603303:RNF146 protein, rat; D044767:Ubiquitin-Protein Ligases; C499321:Parp1 protein, mouse; C499322:Parp1 protein, rat; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases