The Lautenberg Center for General and Tumor Immunology, The Faculty of Medicine, The Hebrew University Medical School, IMRIC, Jerusalem, Israel.
The Institute for Drug Research, Hebrew University Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
Nat Commun. 2021 Apr 6;12(1):2061. doi: 10.1038/s41467-021-21983-x.
Stress can induce cell surface expression of MHC-like ligands, including MICA, that activate NK cells. Human cytomegalovirus (HCMV) glycoprotein US9 downregulates the activating immune ligand MICA008 to avoid NK cell activation, but the underlying mechanism remains unclear. Here, we show that the N-terminal signal peptide is the major US9 functional domain targeting MICA008 to proteasomal degradation. The US9 signal peptide is cleaved with unusually slow kinetics and this transiently retained signal peptide arrests MICA008 maturation in the endoplasmic reticulum (ER), and indirectly induces its degradation via the ER quality control system and the SEL1L-HRD1 complex. We further identify an accessory, signal peptide-independent US9 mechanism that directly binds MICA008 and SEL1L. Collectively, we describe a dual-targeting immunoevasin, demonstrating that signal peptides can function as protein-integral effector domains.
应激可诱导 MHC 样配体（包括 MICA）在细胞表面表达，从而激活 NK 细胞。人巨细胞病毒（HCMV）糖蛋白 US9 下调激活免疫配体 MICA008 以避免 NK 细胞激活，但潜在机制尚不清楚。本研究表明，N 端信号肽是 US9 靶向 MICA008 至蛋白酶体降解的主要功能域。US9 信号肽的切割动力学异常缓慢，这使信号肽暂时保留，导致 MICA008 在 ER 中成熟受阻，并通过 ER 质量控制系统和 SEL1L-HRD1 复合物间接诱导其降解。我们进一步鉴定了一种辅助的、不依赖信号肽的 US9 机制，该机制可直接结合 MICA008 和 SEL1L。综上，本研究描述了一种双重靶向免疫逃逸物，表明信号肽可作为蛋白整合效应结构域发挥作用。
