G9a/GLP methyltransferase inhibits autophagy by methylation-mediated ATG12 protein degradation

Previous studies showed that G9a, a lysine methyltransferase, inhibits autophagy by repressing the transcription of autophagy genes. Here, we demonstrate a novel mechanism whereby G9a/GLP inhibits autophagy through post-translational modification of ATG12, a protein critical for the initiation of autophagosome formation. Under non-stress conditions, G9a/GLP directly methylates ATG12. The methylated ATG12 undergoes ubiquitin-mediated protein degradation, thereby suppressing autophagy induction. By contrast, under stress conditions that elevate intracellular Ca2+ levels, the activated calpain system cleaves the G9a/GLP proteins, leading to G9a/GLP protein degradation. The reduced G9a/GLP levels allow ATG12 to accumulate and form the ATG12-ATG5 conjugate, thus expediting autophagy initiation. Collectively, our findings reveal a distinct signaling pathway that links 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.

既往研究业已表明，G9a（一种赖氨酸甲基转移酶）通过抑制自噬基因的转录来抑制自噬过程。在本研究中，我们揭示了G9a/GLP通过ATG12的翻译后修饰，抑制自噬的新机制，而ATG12是一种对于自噬体形成启动至关重要的蛋白质。在非应激状态下，G9a/GLP直接甲基化ATG12。甲基化的ATG12在泛素介导的蛋白质降解过程中被降解，从而抑制自噬诱导。相反，在细胞内Ca2+水平升高的应激条件下，激活的钙蛋白酶系统裂解G9a/GLP蛋白，导致G9a/GLP蛋白降解。G9a/GLP水平的降低使ATG12得以积累并形成ATG12-ATG5共价复合物，从而加速自噬的启动。综合来看，我们的研究揭示了将涉及Ca2+/钙蛋白酶的细胞应激反应与G9a/GLP介导的自噬调控联系起来的独特信号通路。此外，我们的模型提出，ATG12的甲基化状态是控制自噬诱导的分子变阻器。