Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
HHMI, University of Texas Southwestern Medical Center, Dallas, TX 75390.
Proc Natl Acad Sci U S A. 2024 Dec 3;121(49):e2410205121. doi: 10.1073/pnas.2410205121. Epub 2024 Nov 27.
Autophagy is a key innate immune defense mechanism in intestinal epithelial cells. Bacterial invasion of epithelial cells activates antibacterial autophagy through a process that requires the innate immune adaptor protein MYD88, yet how MYD88 signaling connects to the autophagy machinery is unknown. Here, we show that the mouse intestinal pathogen enterica Serovar Typhimurium ( Typhimurium) triggers MYD88 signaling that regulates binding of the anti-autophagy factor B cell lymphoma 2 (BCL2) to the essential autophagy protein Beclin1 (BECN1) in small intestinal enterocytes, a key epithelial cell lineage. infection activated the kinase c-Jun N-terminal protein kinase 1 (JNK1) downstream of MYD88. JNK1 induced enterocyte BCL2 phosphorylation, promoting dissociation of the inhibitory BCL2-BECN1 complex and releasing BECN1 to initiate autophagy. Mice with BCL2 phosphorylation site mutations that prevent BCL2-BECN1 dissociation showed increased invasion of enterocytes and dissemination to extraintestinal sites. These findings reveal that BCL2 links MYD88 signaling to enterocyte autophagy initiation, providing mechanistic insight into how invading bacteria trigger autophagy in the intestinal epithelium.
自噬是肠道上皮细胞中一种关键的固有免疫防御机制。细菌入侵上皮细胞会通过一种需要先天免疫衔接蛋白 MYD88 的过程激活抗菌自噬，但 MYD88 信号如何与自噬机制连接尚不清楚。在这里，我们表明，肠道病原体鼠伤寒沙门氏菌（ Typhimurium）触发 MYD88 信号，调节抗自噬因子 B 细胞淋巴瘤 2（BCL2）与必需自噬蛋白 Beclin1（BECN1）在小肠上皮细胞中的结合，这是一种关键的上皮细胞谱系。 感染激活了 MYD88 下游的激酶 c-Jun N 端蛋白激酶 1（JNK1）。JNK1 诱导肠细胞 BCL2 磷酸化，促进抑制性 BCL2-BECN1 复合物的解离，并释放 BECN1 以启动自噬。BCL2 磷酸化位点突变阻止 BCL2-BECN1 解离的小鼠显示肠细胞中 侵袭增加，并传播到肠外部位。这些发现揭示了 BCL2 将 MYD88 信号与肠细胞自噬起始联系起来，为入侵细菌如何在肠道上皮细胞中触发自噬提供了机制上的见解。
