Joseph Garcia, MD, PhD

Our overall objective is to identify the molecular basis and biological role for key stress signaling pathways in mammals. A focus of our studies is Hypoxia Inducible Factor 2 (HIF-2), the second of three related and highly conserved stress-activated transcription factors in vertebrates. We use molecular, biochemical, cellular, and physiological approaches to define the HIF-2 signaling axis. Over the years, our laboratory has made novel contributions to the HIF-2 field that have advanced our overall understanding of stress signaling in mammals. HIF-2 signaling is activated by environmental stress associated with oxygen or glucose deprivation. We determined that HIF-2 is acetylated during stress states by Cbp, an acetyltransferase that modifies non-histone and histone proteins in a select manner, and deacetylated by Sirtuin 1, a genetic regulator involved in multiple cellular stress responses. We subsequently identified the rate-limiting step for Cbp-mediated acetylation of HIF-2 as availability of a specific pool of acetyl CoA, which in turn is selectively produced by the acetate-dependent acetyl CoA generator Acss2. We discovered that Acss2, a predominantly cytosolic protein, mediates nuclear signaling by translocating or enriching in the nucleus following oxygen or glucose deprivation. We are actively engaged in discerning how Acss2 mediates its subcellular specific roles in mammals.