Ma Qinmei, Yu Jialin, Liu Li, Ma Xiaoyan, Zhang Jiaxue, Zhang Jiamei, Wang Xiaoping, Deng Guangcun, Wu Xiaoling
School of Life Science, Ningxia University, Yinchuan, NingXia, 750021, China.
Key Lab of Ministry of Education for Protection and Utilization of Special Biological Resources in Western China, Ningxia University, Yinchuan, NingXia, 750021, China.
Cell Death Discov. 2023 Nov 28;9(1):427. doi: 10.1038/s41420-023-01731-4.
Tumor necrosis factor receptor-associated factor 6 (TRAF6) is an E3 ubiquitin ligase that is extensively involved in the autophagy process by interacting with diverse autophagy initiation and autophagosome maturation molecules. However, whether TRAF6 interacts with lysosomal proteins to regulate Mycobacterium-induced autophagy has not been completely characterized. Herein, the present study showed that TRAF6 interacted with lysosomal key proteins Rab7 through RING domain which caused Rab7 ubiquitination and subsequently ubiquitinated Rab7 binds to STX17 (syntaxin 17, a SNARE protein that is essential for mature autophagosome), and thus promoted the fusion of autophagosomes and lysosomes. Furthermore, TRAF6 enhanced the initiation and formation of autophagosomes in Mycobacterium-induced autophagy in both BMDMs and RAW264.7 cells, as evidenced by autophagic flux, colocalization of LC3 and BCG, autophagy rates, and autophagy-associated protein expression. Noteworthy to mention, TRAF6 deficiency exacerbated lung injury and promoted BCG survival. Taken together, these results identify novel molecular and cellular mechanisms by which TRAF6 positively regulates Mycobacterium-induced autophagy.
肿瘤坏死因子受体相关因子6（TRAF6）是一种E3泛素连接酶，通过与多种自噬起始和自噬体成熟分子相互作用，广泛参与自噬过程。然而，TRAF6是否与溶酶体蛋白相互作用以调节分枝杆菌诱导的自噬尚未完全明确。在此，本研究表明TRAF6通过其环指结构域与溶酶体关键蛋白Rab7相互作用，导致Rab7泛素化，随后泛素化的Rab7与STX17（ syntaxin 17，一种对成熟自噬体至关重要的SNARE蛋白）结合，从而促进自噬体与溶酶体的融合。此外，通过自噬通量、LC3与卡介苗的共定位、自噬率以及自噬相关蛋白表达等指标证实，TRAF6增强了骨髓来源的巨噬细胞（BMDMs）和RAW264.7细胞中分枝杆菌诱导的自噬过程中自噬体的起始和形成。值得一提的是，TRAF6缺陷加剧了肺损伤并促进了卡介苗的存活。综上所述，这些结果揭示了TRAF6正向调节分枝杆菌诱导的自噬的新的分子和细胞机制。
