title: Signal peptide peptidase is required for dislocation from the endoplasmic reticulum.
abstract: 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.
authors.affiliation: Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Joana
authors.initials: J
authors.lastname: Loureiro
authors.forename: Brendan N
authors.initials: BN
authors.lastname: Lilley
authors.forename: Eric
authors.initials: E
authors.lastname: Spooner
authors.forename: Vanessa
authors.initials: V
authors.lastname: Noriega
authors.forename: Domenico
authors.initials: D
authors.lastname: Tortorella
authors.forename: Hidde L
authors.initials: HL
authors.lastname: Ploegh
mesh_terms: D000595:Amino Acid Sequence; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D003587:Cytomegalovirus / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014759:Viral Envelope Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D015395:Histocompatibility Antigens Class I; D016601:RNA-Binding Proteins; C074546:US11 protein, herpesvirus; C118670:US2 protein, Varicellovirus; D014759:Viral Envelope Proteins; D014764:Viral Proteins; D016282:Aspartic Acid Endopeptidases; C460085:signal peptide peptidase; D046988:Proteasome Endopeptidase Complex