Franco Luis H, Nair Vidhya R, Scharn Caitlyn R, Xavier Ramnik J, Torrealba Jose R, Shiloh Michael U, Levine Beth
Center for Autophagy Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Cell Host Microbe. 2017 Jan 11;21(1):59-72. doi: 10.1016/j.chom.2016.11.002. Epub 2016 Dec 22.
During antibacterial autophagy, ubiquitination of intracellular bacteria recruits proteins that mediate bacterial delivery to the lysosome for degradation. Smurf1 is an E3 ubiquitin ligase whose role in selective bacterial autophagy is unknown. We show that Smurf1 facilitates selective autophagy of the human pathogen Mycobacterium tuberculosis (Mtb). Smurf1 macrophages are defective in recruiting polyubiquitin, the proteasome, the ubiquitin-binding autophagy adaptor NBR1, the autophagy protein LC3, and the lysosomal marker LAMP1 to Mtb-associated structures and are more permissive for Mtb growth. This function of Smurf1 requires both its ubiquitin-ligase and C2 phospholipid-binding domains, and involves K48- rather than K63-linked ubiquitination. Chronically infected Smurf1 mice have increased bacterial load, increased lung inflammation, and accelerated mortality. SMURF1 controls Mtb replication in human macrophages and associates with bacteria in lungs of patients with pulmonary tuberculosis. Thus, Smurf1 is required for selective autophagy of Mtb and host defense against tuberculosis infection.
在抗菌自噬过程中，细胞内细菌的泛素化作用会募集一些蛋白质，这些蛋白质介导细菌被递送至溶酶体进行降解。Smurf1是一种E3泛素连接酶，其在选择性细菌自噬中的作用尚不清楚。我们发现Smurf1促进人类病原体结核分枝杆菌（Mtb）的选择性自噬。缺乏Smurf1的巨噬细胞在将多聚泛素、蛋白酶体、泛素结合自噬衔接蛋白NBR1、自噬蛋白LC3以及溶酶体标记物LAMP1募集至与Mtb相关的结构方面存在缺陷，并且对Mtb生长更具易感性。Smurf1的这一功能需要其泛素连接酶结构域和C2磷脂结合结构域，且涉及K48连接而非K63连接的泛素化。长期感染的Smurf1基因敲除小鼠细菌载量增加、肺部炎症加剧且死亡率加快。SMURF1在人类巨噬细胞中控制Mtb复制，并与肺结核患者肺部的细菌相关联。因此，Smurf1是Mtb选择性自噬和宿主抵御结核感染所必需的。
