Abstract:
Apoptosis inhibitor 5 (Api5), a known anti-apoptotic protein, is responsible for inhibition of cell death in stressful conditions like serum starvation and DNA damage. Acetylation at K251 is the only known post-translational modification that is responsible for maintaining the stability of Api5. However, the enzymes involved in the regulation of acetylation and de-acetylation of Api5 is yet to be discovered. Our studies demonstrate that p300 histone acetyltransferase and HDAC1 are the enzymes that regulate K251 acetylation-mediated stability of Api5. The de-acetylated and unstable form of Api5 localises to the cytoplasm for proteasomal degradation. Api5 undergoes ubiquitination by FBXO3, FBXO6, and FBXW2 prior to post-translational degradation through the proteasomal pathway. Api5 protein levels have been observed to fluctuate during cell cycle progression. Reduced protein expression of Api5 in the G2-M phase of the cell cycle indicate Api5 to undergo cell cycle-dependent post-translational degradation. However, the pathway and mechanism for this degradation have not been elucidated. We concluded that cell cycle-dependent degradation of Api5 is also through the proteasomal pathway. This post-translational degradation of Api5 in the G2-M phase required Aurora kinase B activity. We also investigated the role of post-translational modifications of Api5 during DNA damage-induced apoptosis. We observed Api5 inhibits DNA damage-induced apoptosis. Once the apoptotic cascade is initiated upon extensive DNA damage, Api5 undergoes proteasomal degradation. This study also revealed ATR to regulate Api5 upon DNA damage-induced apoptosis.
