Epigenetic and Transcriptional Regulation of Autophagy

Macroautophagy (hereafter referred to as autophagy) is an essential self-digestion process to maintain homeostasis and promote survival in response to starvation. Although the components of autophagy in the cytoplasm have been well-studied, little has been known about the fine-tuning mechanism of autophagy through epigenetic regulations. Recently, we identified the histone arginine methyltransferase CARM1 as a new component and followed histone H3R17 dimethylation as a critical epigenetic mark in starvation-induced autophagy. Upon nutrient starvation, CARM1 is stabilized in the nucleus, but not in the cytoplasm, whereas it is constantly degraded under nutrient-rich conditions by the SKP2-containing SCF (SKP1-CUL1-F-box protein) E3 ubiquitin ligase. We further showed that nutrient starvation induces the proteins levels and activity of AMPK in the nucleus. Activated AMPK then phosphorylates FOXO3, leading to SKP2 downregulation and increased CARM1 protein levels in the nucleus. Stabilized CARM1 in turn functions as an essential co-activator of TFEB and regulates the expression of autophagy and lysosomal genes. Our findings provide a conceptual advance that activation of specific epigenetic programs is indispensable for a sustained autophagic response, and shed light on a potential therapeutic targeting of the newly identified AMPK-SKP2-CARM1 signaling axis in autophagy-related diseases.

巨自噬（Macroautophagy），以下简称自噬，是维持细胞稳态、响应饥饿以促进细胞存活的关键自我消化过程。尽管细胞质中的自噬组分已被广泛研究，但人们对表观遗传调控自噬的精细机制仍知之甚少。近期，本团队鉴定出组蛋白精氨酸甲基转移酶（histone arginine methyltransferase）CARM1为新的自噬组分，并证实组蛋白H3R17二甲基化（histone H3R17 dimethylation）是饥饿诱导自噬过程中的关键表观遗传标记。在营养匮乏状态下，CARM1在细胞核内得以稳定，而在细胞质中则无此现象；而在营养充足条件下，CARM1会被含SKP2的SCF（SKP1-CUL1-F-box蛋白）E3泛素连接酶持续降解。本团队进一步研究发现，营养匮乏可诱导细胞核内腺苷酸活化蛋白激酶（AMPK）的蛋白水平与活性升高。活化的腺苷酸活化蛋白激酶随后磷酸化叉头框转录因子O3（FOXO3），进而下调SKP2的表达，使细胞核内CARM1的蛋白水平得以提升。稳定积累的CARM1继而作为转录因子EB（TFEB）的关键共激活因子，调控自噬相关基因与溶酶体基因的表达。本研究成果实现了概念层面的突破：特定表观遗传程序的激活对于维持持续的自噬反应不可或缺，同时也为自噬相关疾病中靶向该新鉴定的AMPK-SKP2-CARM1信号轴的治疗策略提供了理论支撑。