The Mechanism Of The Regulation Of HSL Acetylation By TIP60 Promoting Lipolysis

The HIV-1 Tat-interacting protein 60 kD is the catalytic subunit of the highly conserved NuA4 acetyltransferase complex,which plays critical roles in biological processes including transcriptional regulation,DNA damage repair and cell autophagy.However,it remains unclear whether TIP60 contributes to lipid metabolism.Lipolysis is the process by which FAs and glycerol are hydrolyzed from the glycerol backbone of TAQ which is essential for the normal survival of the body under starvation conditions.At present,HSL is recognized as being largely responsible for the second step of lipolysis,the hydrolysis of DAG to MAG.In this study,we found that the Tip60S86A/S86A mice appeared normal lipolysis under the normal chow diet.However,compared to their WT littermates,Tip60S86A/S86A mice exhibit significantly lower lipolytic activity under starvation conditions.Mechanistically,activated TIP60 directly interacts and acetylates the HSL.In addition,treatment with the TIP60 inhibitor MG149 reduced HSL acetylation.Moreover,the TIP60-S86A mutant showed compromised acetyltransferase activity towards HSL compared with WT-TIP60 indicating that TIP60-Ser86 phosphorylation being necessary for its efficient acetyltransferase activity.Furthermore,treatment of cells with isoproterenol increased HSL acetylation,and this effect was reduced under treatment with MG 149.Further studies revealed that TIP60 can increase the phosphorylation level of HSL at S563 and S660 under starvation conditions,which may affect HSL enzyme activity.More importantly,in response to isoproterenol,HSL translocates from cytoplasm to lipid droplets,inhibition of TIP60 activity strongly diminished the levels of LD lipin 1 under treated conditions.These findings provide new insights into TIP60-mediated HSL acetylation on lipid metabolism,enabling the organism to survive under nutritionally deficient conditions.