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Kaposi's sarcoma-associated herpesvirus (KSHV) has evolved a novel means of evading the human immune system: two KSHV proteins, MIR1 and MIR2, cause immune recognition molecules on the host cell surface to be internalized and degraded in the endosome. But how do MIR1 and MIR2 accomplish this? On page 1265, Coscoy et al. present the surprising finding that the viral proteins ubiquitinate their cellular targets, and that this modification causes the immune recognition molecules MHC-I, B7.2, and ICAM-1 to be endocytosed. In addition to uncovering a new use for ubiquitination, the work identifies the first of a new class of ubiquitin ligases.The authors found that the ubiquitination requires the PHD subfamily zinc finger motifs found in the MIR1 and MIR2 membrane-bound viral proteins. In vitro analysis of MIR2 shows that it is an E3 ubiquitin ligase, making it the first such enzyme found to use a PHD subfamily rather than a RING subfamily zinc finger. MIR1 and MIR2 may interact with immune recognition molecules on the cell surface and ubiquitinate lysine residues in the cytoplasmic domains of the host proteins.
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* }- x8 E5 |( W, g# Z+ V8 xThe substrates of MIR1 and MIR2 are targeted to the endosome rather than the proteosome, so the results add immune recognition molecules to the growing list of proteins whose endocytosis can be regulated by ubiquitination. The two viral proteins were originally identified in a screen for inhibitors of immune recognition, so Coscoy et al. are now searching for additional substrates that might be ubiquitinated by MIR2.
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Another group, studying a MIR1 homologue called MK3 in a murine herpesvirus, has independently determined that MK3 causes the ubiquitination and degradation of mouse MHC-I (Boname, J.M., et al. 2001. Immunity. 15:627–636). In contrast to the situation in KSHV infection, though, MK3-driven ubiquitination targets MHC-I to the proteosome.(MIR2 directs ubiquitination of its targe) |
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发表于 2009-3-5 23:50
发表于 2015-5-27 09:18
