MHC Class I Ubiquitination by a Viral PHD/LAP Finger Protein

Abstract

The murine gamma-herpesvirus-68 K3 (MK3) is a PHD/LAP finger protein that downregulates major histocompatibility complex (MHC) class I expression. In transfected cell lines, MK3 was expressed in the endoplasmic reticulum (ER) membrane, where it bound the cytoplasmic tail of newly synthesized H-2D(b) glycoproteins and targeted them for degradation. Proteasome inhibitors blocked the degradation and led to an accumulation of ubiquitinated H-2D(b). Because this retained its native conformation, ubiquitination preceded any denaturation or dislocation to the cytosol. The PHD/LAP finger of MK3 was not required for H-2D(b) binding but was essential for its ubiquitination and degradation. Thus, gamma-herpesviruses have adapted the cellular PHD/LAP motif to immune evasion, apparently for the catalysis of MHC class I ubiquitination.

Regulation of CD1d expression and function by a herpesvirus infection

“…In earlier studies of MIR-mediated downregulation of MHC class I and B7.2, we (32) and others (38) showed that downregulation of the target proteins is dependent upon the ubiquitination of cytosolic lysine residues in the target. Ubiquitination triggers internalization of these chains and directs the nascent endosome into the multivesicular body (MVB) pathway (39), where its contents are sorted to lysosomes and degraded by lysosomal proteases (28,32).…”

Varicelloviruses avoid T cell recognition by UL49.5-mediated inactivation of the transporter associated with antigen processing

“…MK3, a double-pass transmembrane protein with cytoplasmic N and C termini, targets MHC class I, tapasin, and TAP for proteasomal degradation via a reaction that requires its N-terminal RING finger, a structure that is absent in UL49.5 (26)(27)(28). Unlike mK3, which targets MHC class I heavy chains for degradation by conjugating ubiquitin to their cytoplasmic tails, UL49.5 does not cause degradation of class I molecules.…”

“…This glycoprotein does not affect peptide binding to TAP, but induces conformational changes within the transporter complex that prevent ATP binding and peptide translocation (20,22,23). The murine ␥-herpesvirus 68-encoded K3 protein (mK3) inhibits antigen presentation by destabilizing MHC class I molecules, TAP, and tapasin (26)(27)(28). mK3 carries a cytoplasmic RING finger that catalyzes ubiquitination of substrates, a property essential for targeting MHC class I, TAP, and tapasin for degradation (26)(27)(28).…”

“…The murine ␥-herpesvirus 68-encoded K3 protein (mK3) inhibits antigen presentation by destabilizing MHC class I molecules, TAP, and tapasin (26)(27)(28). mK3 carries a cytoplasmic RING finger that catalyzes ubiquitination of substrates, a property essential for targeting MHC class I, TAP, and tapasin for degradation (26)(27)(28). Thus, ICP47, US6, and mK3 all inactivate the MHC class I peptide-loading complex, but each acts by a different mechanism.…”

Protéines Nef du VIH et K3/K5 du virus associé au sarcoma de Kaposi : des « parasites »de la voie d’endocytose

“…Le virus murin homologue de KSHV, MHV-68, module aussi l'expression de surface du CMH-I par l'intermédiaire de protéines semblables à K3 et K5 (MK3 et MK5) responsables de l'ubiquitinylation des molécules de classe I murines. De façon surprenante, l'effet de cette même modification conduit dans le système murin à une dégradation précoce des molécules néo-synthétisées par le protéasome avant qu'elles ne quittent le réticulum endoplasmique [32]. Une telle diffé-rence dans des systèmes si proches conduit à se poser la question de l'intérêt pour les virus de cibler l'une ou l'autre de ces voies pour aboutir à un résultat apparemment identique.…”