Cowpox virus exploits the endoplasmic reticulum retention pathway to inhibit MHC class I transport to the cell surface.
Major histocompatibility complex (MHC) class I molecules assemble with peptides in the ER lumen and are transported via Golgi to the plasma membrane for recognition by T cells. Inhibiting MHC assembly, transport, and surface expression are common viral strategies of evading immune recognition. Cowpox virus, a clinically relevant orthopoxvirus, downregulates MHC class I expression on infected cells. However, the viral protein(s) and mechanisms responsible are unknown. We identify CPXV203 as a cowpox virus protein that associates with fully assembled MHC class I molecules and blocks their transport through the Golgi. A C-terminal KTEL motif in CPXV203 closely resembles the canonical ER retention motif KDEL and is required for CPXV203 function, indicating that a physiologic pathway is exploited to retain MHC class I in the ER. This viral mechanism for MHC class I downregulation may explain virulence differences between clinical isolates of orthopoxviruses.
Byun
Minji
M
Howard Hughes Medical Institute, Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Wang
Xiaoli
X
Pak
Melissa
M
Hansen
Ted H
TH
Yokoyama
Wayne M
WM
D000818:Animals; D001692:Biological Transport; D002478:Cells, Cultured; D015605:Cowpox / Q000276:immunology* / Q000821:virology*; D015608:Cowpox virus / Q000502:physiology*; D015536:Down-Regulation; D004721:Endoplasmic Reticulum / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D026901:Membrane Transport Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D021381:Protein Transport; D014764:Viral Proteins / Q000378:metabolism
D015395:Histocompatibility Antigens Class I; D026901:Membrane Transport Proteins; D014764:Viral Proteins