Downregulation of cell surface receptors by the K3 family of viral and cellular ubiquitin E3 ligases.
The mK3, K3, and K5 gene products from the gamma2 group of gamma-herpesviruses are the founding members of a family of membrane-associated ubiquitin E3 ligases. As part of the viral immunoevasion strategy, expression of these proteins results in a decrease in cell-surface major histocompatibility complex class I molecules and other immunoreceptors including intercellular adhesion molecule-1, CD86, and CD1d. These viral gene products all possess a characteristic cytosolic N-terminal RING-CH domain, responsible for ubiquitination of the target protein, and two membrane-spanning segments required for substrate specificity. For the majority of substrates, ubiquitination at the cell surface leads to rapid internalization and endolysosomal degradation, while mK3 ubiquitinates class I molecules associated with the peptide-loading complex resulting in proteasome-mediated degradation. Related viral genes with similar functions have been found in poxviruses, suggesting appropriation of these genes from the eukaryotic host. Ten membrane-associated RING-CH (MARCH) human genes with a similar organization have now been identified, and their overexpression leads to ubiquitination and downregulation of a variety of cell-surface immunoreceptors. While all the MARCH proteins are predicted to act as ubiquitin E3 ligases, their physiological role and substrates remain to be defined.
Lehner
Paul J
PJ
Department of Medicine, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, UK. pjl30@cam.ac.uk
Hoer
Simon
S
Dodd
Roger
R
Duncan
Lidia M
LM
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015536:Down-Regulation; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018448:Models, Immunological; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000276:immunology* / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014777:Virus Diseases / Q000276:immunology*
D002352:Carrier Proteins; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D011956:Receptors, Cell Surface; D025801:Ubiquitin; D014764:Viral Proteins; D044767:Ubiquitin-Protein Ligases