Jian Fenglei, Wang Shen, Tian Wenmin, Chen Yang, Wang Shixuan, Li Yan, Ma Cong, Rong Yueguang
School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Disease, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Nat Commun. 2025 Jan 9;16(1):543. doi: 10.1038/s41467-025-55906-x.
Autophagy, a conserved catabolic process implicated in a diverse array of human diseases, requires efficient fusion between autophagosomes and lysosomes to function effectively. Recently, SNAP47 has been identified as a key component of the dual-purpose SNARE complex mediating autophagosome-lysosome fusion in both bulk and selective autophagy. However, the spatiotemporal regulatory mechanisms of this SNARE complex remain unknown. In this study, we found that SNAP47 undergoes acetylation followed by deacetylation during bulk autophagy and mitophagy. The acetylation status of SNAP47 is regulated by the acetyltransferase CBP and the deacetylase HDAC2. Notably, the spatiotemporal regulatory dynamics of SNAP47 acetylation differ between bulk autophagy and mitophagy due to distinct regulation on the activity of acetyltransferase and deacetylase. Acetylated SNAP47 inhibits autophagosome-lysosome fusion by indirectly impeding SNARE complex assembly. Mechanistically, deacetylated SNAP47 recruits HOPS components to autophagic vacuoles independently of STX17 and STX17-SNAP47 interaction, while acetylated SNAP47 inhibits this recruitment, consequently leading to the failure of SNARE complex assembly. Taken together, our study uncovers a SNAP47 acetylation-dependent regulatory mechanism governing autophagosome-lysosome fusion by modulating the recruitment of HOPS to autophagic vacuoles without involving STX17, SNAP47-STX17 interaction and ternary SNARE complex formation.
自噬是一种保守的分解代谢过程，与多种人类疾病相关，它需要自噬体与溶酶体有效融合才能发挥作用。最近，SNAP47已被确定为在巨自噬和选择性自噬中介导自噬体-溶酶体融合的两用SNARE复合体的关键成分。然而，这种SNARE复合体的时空调节机制仍然未知。在本研究中，我们发现SNAP47在巨自噬和线粒体自噬过程中先发生乙酰化，然后去乙酰化。SNAP47的乙酰化状态由乙酰转移酶CBP和去乙酰化酶HDAC2调节。值得注意的是，由于对乙酰转移酶和去乙酰化酶活性的不同调节，SNAP47乙酰化的时空调节动力学在巨自噬和线粒体自噬之间存在差异。乙酰化的SNAP47通过间接阻碍SNARE复合体组装来抑制自噬体-溶酶体融合。机制上，去乙酰化的SNAP47独立于STX17和STX17-SNAP47相互作用将HOPS组分募集到自噬泡，而乙酰化的SNAP47抑制这种募集，从而导致SNARE复合体组装失败。综上所述，我们的研究揭示了一种依赖SNAP47乙酰化的调节机制，该机制通过调节HOPS向自噬泡的募集来控制自噬体-溶酶体融合，而不涉及STX17、SNAP47-STX17相互作用和三元SNARE复合体的形成。
