Function And Molecular Mechanism Of MTORC1-mediatel P300 Activation

Cell metabolism regulates cell growth,differentiation and senescence by altering the production and consumption of energy and macromolecules.Substantial evidence has demonstrated that cell metabolism is regulated by vital protein kinases,located at distinct metabolic steps.Nevertheless,protein acetylation has emerged as an important regulation mechanism of cell metabolism,suggesting a key role of acetyltransferase/deacetylase in this process.One of the most studied histone acetyltransferase(HAT)p300,as well as its related CREB-binding protein(CBP),is evolutionarily conserved and traditionally serves as a transcription coactivator,by acetylating core histones and transcription factors.However,accumulating evidence has demonstrated a role of p300 in various cytoplasmic events through presenting its acetyltransferase activity to cytoplasmic substrates.Recently,it has been suggested that p300 is involved in the regulation of autophagy,a catabolic process required to maintain cellular homeostasis through directing cytoplasmic components for lysosomal degradation.Several autophagy-related proteins(Atgs)including LC3,Atg5 and Atg7 are targeted by p300-mediated acetylation,leading to the inhibition of their autophagic activities.However,the potential mechanism for the inactivation of p300 upon autophagy initiation remains unclear.In this study,we found that the homeostatic sensor mammalian target of rapamycin complex 1(mTORC1)is a direct regulator of p300.mTORCl interacts with p300 on the lysosomes and phosporylates p300 at 4 serine residues located in the C-terminal domain of p300.Mechanistically,phosphorylation by mTORCl disassociates the intra-molecular binding of the inhibitory RING domain to the catalytic HAT domain of p300.Functional analysis demonstrates that mTORC1-dependent phosphorylation is required for p300-mediated autophagy inhibition and transcription activation.Our findings suggest that p300 is a direct target of mTORCl,and this mTORC1-p300 pathway plays a key role in the regulation of cell metabolism by coordinately controlling cell anabolism and catabolism.