Human cytomegalovirus protein US11 provokes an unfolded protein response that may facilitate the degradation of class I major histocompatibility complex products.
The human cytomegalovirus (HCMV) glycoprotein US11 diverts class I major histocompatibility complex (MHC) heavy chains (HC) from the endoplasmic reticulum (ER) to the cytosol, where HC are subjected to proteasome-mediated degradation. In mouse embryonic fibroblasts that are deficient for X-box binding protein 1 (XBP-1), a key transcription factor in the unfolded protein response (UPR) pathway, we show that degradation of endogenous mouse HC is impaired. Moreover, the rate of US11-mediated degradation of ectopically expressed HLA-A2 is reduced when XBP-1 is absent. In the human astrocytoma cell line U373, turning on expression of US11, but not US2, is sufficient to induce a UPR, as manifested by upregulation of the ER chaperone Bip and by splicing of XBP-1 mRNA. In the presence of dominant-negative versions of XBP-1 and activating transcription factor 6, the kinetics of class I MHC HC degradation were delayed when expression of US11 was turned on. The magnitude of these effects, while reproducible, was modest. Conversely, in cells that stably express high levels of US11, the degradation of HC is not affected by the presence of the dominant negative effectors of the UPR. An infection of human foreskin fibroblasts with human cytomegalovirus induced XBP-1 splicing in a manner that coincides with US11 expression. We conclude that the contribution of the UPR is more pronounced on HC degradation shortly after induction of US11 expression and that US11 is sufficient to induce such a response.
Tirosh
Boaz
B
Department of Pathology, Harvard Medical School, 77 Ave. Louis Pasteur, Room 836, Boston MA 02115, USA.
Iwakoshi
Neal N
NN
Lilley
Brendan N
BN
Lee
Ann-Hwee
AH
Glimcher
Laurie H
LH
Ploegh
Hidde L
HL
D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000378:metabolism* / Q000472:pathogenicity; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000096:biosynthesis; D015395:Histocompatibility Antigens Class I / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018832:Molecular Chaperones / Q000096:biosynthesis; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D011489:Protein Denaturation; D012326:RNA Splicing; D016601:RNA-Binding Proteins / Q000378:metabolism*; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D014759:Viral Envelope Proteins; D014764:Viral Proteins / Q000378:metabolism*; D000071717:X-Box Binding Protein 1
D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D015395:Histocompatibility Antigens Class I; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; C074546:US11 protein, herpesvirus; C118670:US2 protein, Varicellovirus; D014759:Viral Envelope Proteins; D014764:Viral Proteins; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse