Department of Life Sciences and Chemistry, Jacobs University, Bremen 28759, Germany.
Department of Medicine Huddinge, Karolinska Institutet, Stockholm 14152, Sweden.
J Cell Sci. 2021 Jun 1;134(11). doi: 10.1242/jcs.257428. Epub 2021 Jun 4.
NKG2D (also known as KLRK1) is a crucial natural killer (NK) cell-activating receptor, and the murine cytomegalovirus (MCMV) employs multiple immunoevasins to avoid NKG2D-mediated activation. One of the MCMV immunoevasins, gp40 (m152), downregulates the cell surface NKG2D ligand RAE-1γ (also known as Raet1c) thus limiting NK cell activation. This study establishes the molecular mechanism by which gp40 retains RAE-1γ in the secretory pathway. Using flow cytometry and pulse-chase analysis, we demonstrate that gp40 retains RAE-1γ in the early secretory pathway, and that this effect depends on the binding of gp40 to a host protein, TMED10, a member of the p24 protein family. We also show that the TMED10-based retention mechanism can be saturated, and that gp40 has a backup mechanism as it masks RAE-1γ on the cell surface, blocking the interaction with the NKG2D receptor and thus NK cell activation.
NKG2D（也称为 KLRK1）是一种关键的自然杀伤（NK）细胞激活受体，而小鼠巨细胞病毒（MCMV）采用多种免疫逃逸机制来避免 NKG2D 介导的激活。MCMV 的免疫逃逸蛋白之一，gp40（m152）下调细胞表面 NKG2D 配体 RAE-1γ（也称为 Raet1c），从而限制 NK 细胞的激活。本研究建立了 gp40 将 RAE-1γ保留在分泌途径中的分子机制。通过流式细胞术和脉冲追踪分析，我们证明 gp40 将 RAE-1γ保留在早期分泌途径中，并且这种效应取决于 gp40 与宿主蛋白 TMED10 的结合，TMED10 是 p24 蛋白家族的成员。我们还表明，基于 TMED10 的保留机制可以被饱和，并且 gp40 具有后备机制，因为它在细胞表面掩盖 RAE-1γ，阻断与 NKG2D 受体的相互作用，从而阻止 NK 细胞的激活。
