G9a/GLP methyltransferases inhibit autophagy by methylation-mediated ATG12 protein degradation

Previous studies showed that a lysine methyltransferase G9a inhibits autophagy by repressing transcription of autophagy genes. Here, we demonstrate a novel mechanism whereby G9a/GLP inhibit autophagy through post-translational modification of ATG12, a protein critical for initiation of autophagosome formation. Under non-stress conditions, G9a/GLP directly methylate ATG12. The methylated ATG12 undergoes ubiquitin-mediated protein degradation, thereby suppressing autophagy induction. By contrast, under stress conditions that elevate intracellular Ca2+ level, the activated calpain system cleaves G9a/GLP proteins, leading to G9a/GLP protein degradation. Consequently, reduced G9a/GLP levels allow accumulation of ATG12 and formation of the ATG12-ATG5 conjugate and LC3II, thus expediting autophagy initiation. Collectively, our findings reveal a distinct signaling pathway linking cellular stress responses involving Ca2+/calpain to G9a/GLP-mediated autophagy regulation. Moreover, our model proposes that the methylation status of ATG12 is a molecular rheostat that controls autophagy induction.