Lapaque Nicolas, Hutchinson James L, Jones Des C, Méresse Stéphane, Holden David W, Trowsdale John, Kelly Adrian P
Division of Immunology, Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom.
Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):14052-7. doi: 10.1073/pnas.0906735106. Epub 2009 Aug 5.
Salmonella typhimurium is a facultative pathogen capable of entering and replicating in both professional and non-professional antigen presenting cells. Control of infection requires MHC class II restricted CD4 T-helper cell responses. Here we show that Salmonella infection induced polyubiquitination of HLA-DR, a post-translational modification that led to removal of mature, peptide loaded, alphabeta dimers from the cell surface. Immature alphabetaIi complexes were unaffected. Surface expression of all class II isotypes, HLA-DP, -DQ, and -DR, was reduced in infected cells, but other cell-surface molecules that traffic through class II peptide loading compartments were unaffected. A Salmonella strain carrying a mutation in ssaV did not induce ubiquitination of class II, implicating Salmonella T3SS-2 effector proteins in the process. T3SS-2 effectors, with established or proposed roles in ubiquitination, were not required for class II down-regulation, suggesting that an additional T3SS-2 effector is involved in regulating MHC class II ubiquitination. Although recognized as a viral immune evasion strategy, here, we demonstrate that bacteria can control surface MHC expression through ubiquitination.
鼠伤寒沙门氏菌是一种兼性病原体，能够在专职和非专职抗原呈递细胞中进入并复制。感染的控制需要MHC II类限制性CD4辅助性T细胞反应。在此我们表明，沙门氏菌感染诱导了HLA-DR的多聚泛素化，这是一种翻译后修饰，导致成熟的、加载了肽的αβ二聚体从细胞表面去除。未成熟的αβIi复合物未受影响。在感染的细胞中，所有II类同种型HLA-DP、-DQ和-DR的表面表达均降低，但通过II类肽加载区室运输的其他细胞表面分子未受影响。携带ssaV突变的沙门氏菌菌株未诱导II类的泛素化，这表明沙门氏菌III型分泌系统2（T3SS-2）效应蛋白参与了该过程。在泛素化中具有既定或推测作用的T3SS-2效应蛋白对于II类下调并非必需，这表明另一种T3SS-2效应蛋白参与调节MHC II类泛素化。尽管泛素化被认为是一种病毒免疫逃避策略，但在此我们证明细菌可以通过泛素化控制表面MHC表达。
