Downregulation of cell surface receptors by the K3 family of viral and cellular ubiquitin E3 ligases

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<jats:p><jats:bold>Summary: </jats:bold> The mK3, K3, and K5 gene products from the γ2 group of γ‐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.</jats:p>

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