Li Sunan, Li Rongrong, Ahmad Iqbal, Liu Xiaomeng, Johnson Silas F, Sun Liangliang, Zheng Yong-Hui
Harbin Veterinary Research Institute, CAAS-Michigan State University Joint Laboratory of Innate Immunity, State Key Laboratory of Veterinary Biotechnology, Chinese Academy of Agricultural Sciences, Harbin, China.
Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI, USA.
Nat Commun. 2022 Apr 26;13(1):2242. doi: 10.1038/s41467-022-30026-y.
HIV-1 must counteract various host restrictions to establish productive infection. SERINC5 is a potent restriction factor that blocks HIV-1 entry from virions, but its activity is counteracted by Nef. The SERINC5 and Nef activities are both initiated from the plasma membrane, where SERINC5 is packaged into virions for viral inhibition or downregulated by Nef via lysosomal degradation. However, it is still unclear how SERINC5 is localized to and how its expression is regulated on the plasma membrane. We now report that Cullin 3-KLHL20, a trans-Golgi network (TGN)-localized E3 ubiquitin ligase, polyubiquitinates SERINC5 at lysine 130 via K33/K48-linked ubiquitination. The K33-linked polyubiquitination determines SERINC5 expression on the plasma membrane, and the K48-linked polyubiquitination contributes to SERINC5 downregulation from the cell surface. Our study reveals an important role of K130 polyubiquitination and K33/K48-linked ubiquitin chains in HIV-1 infection by regulating SERINC5 post-Golgi trafficking and degradation.
HIV-1必须克服各种宿主限制才能建立有效的感染。SERINC5是一种强大的限制因子，可阻止HIV-1从病毒粒子进入细胞，但其活性会被Nef抵消。SERINC5和Nef的活性均从质膜开始，在质膜上，SERINC5被包装到病毒粒子中以抑制病毒，或被Nef通过溶酶体降解而下调。然而，目前尚不清楚SERINC5如何定位到质膜以及其在质膜上的表达如何被调节。我们现在报告，跨高尔基体网络（TGN）定位的E3泛素连接酶Cullin 3-KLHL20通过K33/K48连接的泛素化在赖氨酸130处对SERINC5进行多聚泛素化。K33连接的多聚泛素化决定了SERINC5在质膜上的表达，而K48连接的多聚泛素化则有助于SERINC5从细胞表面下调。我们的研究揭示了K130多聚泛素化和K33/K48连接的泛素链通过调节SERINC5高尔基体后运输和降解在HIV-1感染中的重要作用。
