Mechanism Of Acetyltransferase HBO1 Complex Regulate Autophagy And Sensing Nutrient Status

Autophagy is an essential degradation-recirculation system.Basal autophagy maintains cellular homeostasis under normal conditions,stress such as nutrition deprivation can activate autophagy.In mammalin cells,energy status regulates autophagy through some key kinases(such as AMPK,m TORC1)or some important intermediates(such as acetyl-co A,NAD+).Acetyl-coenzyme A serves as acetyl-group donor for protein acetylation.Nutrient starvation can induce the decreasing of acetyl-co A level and cause the reduction of many cytosolic proteins acetylation.Changing of cytosolic acetyl-co A concentration can affect autophagy directly,and many acetylatransferase and deacetylase play vital roles in autophagy regulation.HBO1 is a member of MYST acetyltransferase family,it can form complexes with different scaffold protein(JADE1/2/3 or BRPF1/2/3).It has histone H3/H4 acetyltransferase activity and promotes gene transcription.Here we report that HBO1 can negatively regulate autophagy,and inhibit autophagy in an enzymatic dependent manner.We showed that HBO1/JADE2 complex which mainly localized in cytosol could inhibit autophagy during autophagy initiation stage.Further studies revealed that deletion of HBO1 resulted in increasing protein level of ULK1(a serine/threonine kinase critical for autophagy initiation)which would promote autophagy initiation.HBO1/JADE2 complex interacts with ULK1 and catalyzes its acetylation at K132 and K140.The acetylatiom of these two sites on ULK1 inhibits its kinase activity and promotes its degradation via proteasome pathway,which eventually inhibit autophagy initation.Besides,HBO1/JADE2 complex can directly sense energy deprivation through the change of acetylation level of JADE2 itself.JADE2 is acetylated by HBO1 and deacetylated by Sirt1.Glucose starvation or amino acid starvation could induce the decreasing of JADE2acetylation via acetyl-co A reduction and promote its degradation via proteasomepathway,this resulted the disassociation and degradation of the HBO1/JADE2 complex,and autophagy initiation was activated.Together,our results demonstrated HBO1 is a novel autophagy regulator,cytolic HBO1/JADE2 complex regulate ULK1 stability and activity.JADE2 can sense the cellular nutrient status via change of acetylco A level.And our study proved that nutrient-acetyl-co A-HBO1 pathway play a vital role in autophagy regulation and maintaining of cellular homeostasis.