Loureiro Joana, Lilley Brendan N, Spooner Eric, Noriega Vanessa, Tortorella Domenico, Ploegh Hidde L
Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Nature. 2006 Jun 15;441(7095):894-7. doi: 10.1038/nature04830. Epub 2006 May 31.
Human cytomegalovirus (HCMV) prevents the display of class I major histocompatibility complex (MHC) peptide complexes at the surface of infected cells as a means of escaping immune detection. Two HCMV-encoded immunoevasins, US2 and US11, induce the dislocation of class I MHC heavy chains from the endoplasmic reticulum membrane and target them for proteasomal degradation in the cytosol. Although the outcome of the dislocation reactions catalysed is similar, US2 and US11 operate differently: Derlin-1 is a key component of the US11 but not the US2 pathway. So far, proteins essential for US2-dependent dislocation have not been identified. Here we compare interacting partners of wild-type US2 with those of a dislocation-incompetent US2 mutant, and identify signal peptide peptidase (SPP) as a partner for the active form of US2. We show that a decrease in SPP levels by RNA-mediated interference inhibits heavy-chain dislocation by US2 but not by US11. Our data implicate SPP in the US2 pathway and indicate the possibility of a previously unknown function for this intramembrane-cleaving aspartic protease in dislocation from the endoplasmic reticulum.
人类巨细胞病毒（HCMV）会阻止I类主要组织相容性复合体（MHC）肽复合物在受感染细胞表面的展示，以此作为逃避免疫检测的一种手段。两种HCMV编码的免疫逃逸蛋白，US2和US11，会诱导I类MHC重链从内质网膜上错位，并将它们靶向胞质溶胶中的蛋白酶体进行降解。尽管所催化的错位反应结果相似，但US2和US11的作用方式不同：Derlin-1是US11途径而非US2途径的关键组成部分。到目前为止，尚未确定US2依赖性错位所必需的蛋白质。在这里，我们比较了野生型US2与无错位能力的US2突变体的相互作用伙伴，并鉴定出信号肽肽酶（SPP）是活性形式的US2的伙伴。我们表明，通过RNA介导的干扰降低SPP水平会抑制US2介导的重链错位，但不会抑制US11介导的重链错位。我们的数据表明SPP参与了US2途径，并表明这种膜内裂解天冬氨酸蛋白酶在内质网错位过程中具有先前未知功能的可能性。
