Ubiquitin-dependent downregulation of cell surface proteins by PHD ubiquitin ligases

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Ubiquitylation events have also been reported to play a key role in the downregulation of cell surface proteins during host immunity system evasion following infection with Kaposi's sarcoma-associated herpes virus (KSHV). KHSV is a recently identified herpes virus responsible for Kaposi's sarcoma, a neoplasm common in individuals suffering from AIDS. After viral infection, major histocompatibility complex (MHC) class I molecules and other molecules (B7-2 and ICAM-1) involved in immune recognition are rapidly downregulated. These molecules are efficiently synthesized and targeted to the plasma membrane, but then rapidly undergo endocytosis followed by degradation in the lysosomes. The viral genome contains two genes, K3 and K5, encoding transmembrane proteins (now named modulator of immune recognition MIR1 and MIR2) with cytoplasmic PHD domains. MIR1 and MIR2 were reported to promote the PHD-dependent cell-surface ubiquitylation of MHC Class I, B7-1 and ICAM-1 [145, 146]. Mutation of the two lysine residues in the cytosolic tail of MHC class I molecules blocks both MHC class I ubiquitylation and downregulation [145, 146]. The transmembrane segment of MIR2 plays a critical role in target recognition, and the transmembrane and juxtamembrane regions of the target MHC class I molecule make a key contribution to recognition by the MIR proteins [145].

Analysis of the sequences of other viral genomes has indicated that transmembrane PHD-containing proteins are present in a considerable number of DNA viruses of the herpesvirus and poxvirus families, and it was predicted that some of these proteins could act as E3 involved in trafficking events [14]. Indeed, M153R, a PHD-containing protein of poxviruses, homolog to K3 and K5 downregulates the T-cell coreceptor CD4 and MHC-I in an ubiquitin-dependent way [147]. The discovery of transmembrane human proteins homolog to K3/K5, membrane-associated RING-CH (MARCH) proteins, suggested that they might play similar roles, an hypothesis which was tested with known substrates of the viral K3 family. Two closely related proteins, MARCH-IV and MARCH-IX, reduced surface expression of MHC-I molecules whereas MHC-I molecules lacking lysines in their cytoplasmic tail were resistant to downregulation [148]. The functional similarity of the MARCH family and the K3 family suggests that the viral immune evasion proteins were derived from MARCH proteins, a novel family of transmembrane ubiquitin ligases.