The trafficking and regulation of membrane receptors by the RING-CH ubiquitin E3 ligases.
Ubiquitylation of membrane receptors is recognised as a critical post-translational modification, governing their regulation and function. Following ubiquitylation, membrane proteins may be internalised, recycled or degraded via lysosomal or proteasomal pathways. Viruses have appropriated these cellular pathways as a mechanism of immune evasion. RING (really interesting new gene)-CH ubiquitin E3 ligases were initially identified from the Kaposi's associated herpesvirus (KSHV) and their founding members, K3 and K5, downregulate several critical immunoreceptors to prevent detection by the host immune system. K3 promotes formation of lysine-63 linked polyubiquitin chains on MHC Class I, signalling Class I internalisation and endolysosomal degradation. K5 targets multiple immunoreceptors, including MHC Class I, CD86, intracellular adhesion molecule (ICAM) 1 and MHC Class I-related chain (MIC)-A/B, thereby preventing detection from cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. The cellular homologues of K3 and K5, the Membrane Associated RING-CH (MARCH) genes, represent eleven proteins that also appear to be important in the downregulation of membrane receptors. While overexpression of several MARCH genes downregulate cell surface receptors such as MHC Class I, MHC Class II, CD86 and ICAM 1, determining their physiological roles has proved difficult. Elucidating the transcriptional regulation, localisation and trafficking of MARCH genes may provide insights into their cellular functions.
Nathan
James A
JA
Department of Medicine, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB20XY, UK. jan33@cam.ac.uk
Lehner
Paul J
PJ
D000818:Animals; D003602:Cytotoxicity, Immunologic / Q000276:immunology / Q000502:physiology; D015536:Down-Regulation; D011992:Endosomes / Q000378:metabolism; D019288:Herpesvirus 8, Human / Q000276:immunology / Q000502:physiology; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D011971:Receptors, Immunologic / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*; D054875:Ubiquitination; D014764:Viral Proteins / Q000378:metabolism
D015395:Histocompatibility Antigens Class I; D017874:Immediate-Early Proteins; C456022:K3 protein, Kaposi's sarcoma-associated herpesvirus; C405867:K5 protein, Human herpesvirus 8; D011971:Receptors, Immunologic; D014764:Viral Proteins; D044767:Ubiquitin-Protein Ligases