Abstract 361: Regulation of Activity of Apoptosis Inducing Factor by SUMO Conjugation

Abstract

Apoptosis inducing factor (AIF), a mitochondrial oxidoreductase, is primarily involved in maintaining mitochondrial function. However, in response to apoptotic insults, AIF is released from mitochondria via cleavage and relocates to the nucleus, where it binds chromatin, subsequently causing its condensation and cell death. Thus, AIF plays an important role in both cell survival and death. The regulatory pathways/signaling events that govern the key step of AIF translocation and activity in cell death are not completely deciphered. SUMO conjugation, a highly conserved posttranslational modification, plays an important role in cardiac homeostasis. Herein, we report AIF as a novel SUMO substrate, and SENP5, a SUMO deconjugation enzyme, increased cardiomyocyte death once overexpressed in the mouse hearts, which coincided with an increase level of truncated AIF in cytosol. In line with the above findings, adenoviral mediated transduction of SENP5 wild type (wt), but not the C713L mutant, the latter of which lacks de-sumoylation activity, triggered cell death and AIF nuclear occupancy. Also, the SENP5-wt, but not the catalytically inactive mutant, de-sumoylated AIF. We further identified lysine residue 89 (K89) on AIF as one of the major SUMO attachment sites, and mutation of K89 to arginine (K89R) promoted AIF nuclear translocation in AC16, a cardiac cell line, and necrosis in L929 cells induced by TNFα/Z-vad-fmk. Our findings provide a novel mechanism by which SUMO conjugation is involved in mediating the function of AIF, which is important for cardiomyocyte survival and death.