MOLECULAR MECHANISMS UNDERLYING HDACIs-INDUCED AUTOPHAGY AND LYSOSOMAL ACTIVATION

Abstract

AUTOPHAGY IS AN EVOLUTIONARILY CONSERVED PROCESS IN WHICH CELLULAR PROTEINS AND ORGANELLES ARE ENGULFED IN AUTOPHAGOSOME WHICH THEN FUSE WITH LYSOSOME TO FORM AUTOLYSOSOME FOR DEGRADATION. AT PRESENT, HISTONE DEACETYLASE INHIBITORS (HDACIS) ARE KNOWN TO INDUCE AUTOPHAGY IN CELLS THROUGH INHIBITION OF MECHANISTIC TARGET OF RAPAMYCIN (MTOR) PATHWAY. FORKHEAD BOX O1 (FOXO1), AN IMPORTANT TRANSCRIPTION FACTOR REGULATED BY AKT, IS ALSO KNOWN TO PLAY A ROLE IN AUTOPHAGY INDUCTION. AT PRESENT, THE ROLE OF FOXO1 IN THE HDACIS-INDUCED AUTOPHAGY HAS NOT BEEN REPORTED. AT THE LATE STAGE OF AUTOPHAGY, AUTOPHAGOSOME IS FUSED WITH LYSOSOME AND UNDERGOES LYSOSOME-DEPENDENT DEGRADATION. THUS, UNDERSTANDING THE MOLECULAR MECHANISMS CONTROLLING LYSOSOMAL FUNCTION IS CRITICALLY IMPORTANT. TRANSCRIPTION FACTOR EB (TFEB) IS A MASTER REGULATOR OF LYSOSOMAL BIOGENESIS, FUNCTION AND AUTOPHAGY. THE TRANSCRIPTIONAL ACTIVITY OF TFEB IS MAINLY CONTROLLED BY ITS PHOSPHORYLATION MEDIATED BY MTOR. HOWEVER, IT I