Acyl-CoA Binding Domain Containing 3 Modulates NAD{+} Metabolism through Activating Poly(ADP-ribose) Polymerase 1

Nicotinadmide adenine dinucleotide (NAD+) plays essential roles in cellular energy homeostasis and redox state functioning as a cofactor along the glycolysis and citric acid cycle pathways. Recent discoveries indicated that, through the NAD+-consuming enzymes, this molecule may be also involved in many other cellular and biological outcomes such as chromatin remodeling, gene transcription, genomic integrity, cell division, calcium signaling, circadian clock and pluripotency. Poly(ADP-ribose) polymerase 1 (PARP1) is such an enzyme, and dysfunctional PARP1 has been linked with the onset and development of various human diseases, including cancer, aging, traumatic brain injury, atherosclerosis, diabetes and inflammation. In the present study, we showed that over-expressed acyl-CoA binding domain containing 3 (ACBD3), a Golgi-bound protein, significantly reduce cellular NAD+ content via enhancing PARP1’s polymerase activity and enhancing auto-modification of the enzyme in a DNA damage-independent manner. We identified that ERK1/2 as well as de novo fatty acid biosynthesis pathways are involved in ACBD3-mediated activation of PARP1. Importantly, oxidative stress-induced PARP1 activation is greatly attenuated by knocking down ACBD3 gene. Taken together, these findings suggest that ACBD3 has prominent impacts on the cellular NAD+ metabolism via regulating PARP1 activation-dependent auto-modification and thus cell metabolism and function.