Membrane-specific, host-derived factors are required for US2-and US11-mediated degradation of major histocompatibility complex class I molecules

被引:54
作者
Furman, MH [1 ]
Ploegh, HL [1 ]
Tortorella, D [1 ]
机构
[1] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA
关键词
D O I
10.1074/jbc.M109765200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Human cytomegalovirus encodes two glycoproteins, US2 and US11, that target major histocompatibility complex (MHC) class I heavy chains for proteasomal degradation. We have developed a mRNA-dependent cell-free system that recapitulates US2- and US11-mediated degradation of MHC class I heavy chains. Microsomes support the degradation of MHC class I heavy chains in the presence of US2 or US11 in a cytosol-dependent manner. In vitro, the glycosylated heavy chain is exported from the microsomes. A deglycosylated breakdown intermediate of the heavy chain identical to that generated in intact cells accumulates in soluble form in the presence of proteasome inhibitors. Microsomes derived from the U373 astrocytoma cell line are far more effective than canine-derived membranes in supporting this US2- or US11-dependent reaction. In contrast, the HIV-encoded Vpu membrane protein can cause the destruction of CD4 from either human- or canine-derived membranes. Using the in vitro system, we show that a truncation mutant of US2 that lacks the cytosolic domain is unable to catalyze degradation, whereas a similar truncation of US11 continues to catalyze degradation of class I heavy chains. Therefore, US2 requires both transmembrane and cytosolic interactions to trigger dislocation of heavy chains, whereas US11 relies on the transmembrane do. main to target heavy chains. US2 and US11 thus utilize different targeting mechanisms for class I degradation.
引用
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页码:3258 / 3267
页数:10
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