Control of infection by LC3-associated phagocytosis, CASM, and detection of raised vacuolar pH by the V-ATPase-ATG16L1 axis.
Control of infection by LC3-associated phagocytosis, CASM, and detection of raised vacuolar pH by the V-ATPase-ATG16L1 axis.
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DOI：
10.1126/sciadv.abn3298
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发表时间：
2022-10-28
期刊：
影响因子：
13.6
通讯作者：
中科院分区：
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将病原体运送到溶酶体进行降解提供了抵抗感染的重要防御。当LC3与含有病原体的核内体和吞噬体结合以促进与溶酶体的融合时，降解增强。在吞噬细胞中，TLR信号和Rubicon激活LC3相关吞噬（LAP），其中NADPH氧化酶的稳定导致持续的ROS产生和空泡pH升高。pH升高触发空泡atp酶在空泡膜上的组装，并结合ATG16L1以招募核心LC3偶联复合物（ATG16L1:ATG5-12）。V-ATPase-ATG16L1轴在非吞噬细胞中也被激活，将LC3结合到含有细胞外微生物的核内体上。当病原体通过形成孔的毒素和蛋白质、磷脂酶或专门的分泌系统提高液泡pH值时，它们为LC3的募集提供了额外的信号。许多微生物分泌毒力因子来抑制ROS的产生和/或V-ATPase-ATG16L1轴，以减缓LC3的招募并避免溶酶体的降解。LC3与含有病原体的液泡结合为自噬蛋白控制感染提供了另一种途径。
The delivery of pathogens to lysosomes for degradation provides an important defense against infection. Degradation is enhanced when LC3 is conjugated to endosomes and phagosomes containing pathogens to facilitate fusion with lysosomes. In phagocytic cells, TLR signaling and Rubicon activate LC3-associated phagocytosis (LAP) where stabilization of the NADPH oxidase leads to sustained ROS production and raised vacuolar pH. Raised pH triggers the assembly of the vacuolar ATPase on the vacuole membrane where it binds ATG16L1 to recruit the core LC3 conjugation complex (ATG16L1:ATG5-12). This V-ATPase-ATG16L1 axis is also activated in nonphagocytic cells to conjugate LC3 to endosomes containing extracellular microbes. Pathogens provide additional signals for recruitment of LC3 when they raise vacuolar pH with pore-forming toxins and proteins, phospholipases, or specialized secretion systems. Many microbes secrete virulence factors to inhibit ROS production and/or the V-ATPase-ATG16L1 axis to slow LC3 recruitment and avoid degradation in lysosomes. Conjugation of LC3 to vacuoles containing pathogens provides alternative ways for autophagy proteins to control infection.
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