Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
Cell Host Microbe. 2012 Dec 13;12(6):778-90. doi: 10.1016/j.chom.2012.10.019.
Several species of pathogenic bacteria replicate within an intracellular vacuolar niche. Bacteria that escape into the cytosol are captured by the autophagic pathway and targeted for lysosomal degradation, representing a defense against bacterial exploitation of the host cytosol. Autophagic capture of Salmonella Typhimurium occurs predominantly via generation of a polyubiquitin signal around cytosolic bacteria, binding of adaptor proteins, and recruitment of autophagic machinery. However, the components mediating bacterial target selection and ubiquitination remain obscure. We identify LRSAM1 as the E3 ligase responsible for anti-Salmonella autophagy-associated ubiquitination. LRSAM1 localizes to several intracellular bacterial pathogens and generates the bacteria-associated ubiquitin signal; these functions require LRSAM1's leucine-rich repeat and RING domains, respectively. Using cells from LRSAM1-deficient individuals, we confirm that LRSAM1 is required for ubiquitination associated with intracellular bacteria but dispensable for ubiquitination of aggregated proteins. LRSAM1 is therefore a bacterial recognition protein and ubiquitin ligase that defends the cytoplasm from invasive pathogens.
几种致病细菌在细胞内的空泡龛位中复制。逃入细胞质的细菌被自噬途径捕获，并靶向溶酶体降解，这代表了宿主细胞质免受细菌利用的防御机制。沙门氏菌 Typhimurium 的自噬捕获主要通过在胞质细菌周围生成多泛素信号、衔接蛋白结合和招募自噬机制来实现。然而，介导细菌靶标选择和泛素化的成分仍然不清楚。我们确定 LRSAM1 是负责抗沙门氏菌自噬相关泛素化的 E3 连接酶。LRSAM1 定位于几种细胞内细菌病原体，并生成与细菌相关的泛素信号；这些功能分别需要 LRSAM1 的亮氨酸丰富重复和 RING 结构域。使用来自 LRSAM1 缺陷个体的细胞，我们证实 LRSAM1 是与细胞内细菌相关的泛素化所必需的，但对于聚集蛋白的泛素化是可有可无的。因此，LRSAM1 是一种细菌识别蛋白和泛素连接酶，可保护细胞质免受入侵病原体的侵害。
