Journal
MEDICAL MICROBIOLOGY AND IMMUNOLOGY
Volume 204, Issue 3, Pages 383-394Publisher
SPRINGER
DOI: 10.1007/s00430-015-0414-1
Keywords
Adapter protein (AP2); Cargo sorting; Clathrin-mediated endocytosis; Endocytosis motif; Immune evasion; Tyrosine-based motif YXX Phi
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Funding
- Deutsche Forschungsgemeinschaft [SFB490]
- young investigator program MAIFOR of the University Medical Center Mainz
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Viruses have evolved proteins that bind immunologically relevant cargo molecules at the cell surface for their downmodulation by internalization. Via a tyrosine-based sorting motif YXXI broken vertical bar in their cytoplasmic tails, they link the bound cargo to the cellular adapter protein-2 (AP2), thereby sorting it into clathrin-triskelion-coated pits for accelerated endocytosis. Downmodulation of CD4 molecules by lentiviral protein NEF represents the most prominent example. Based on connecting cargo to cellular adapter molecules, such specialized viral proteins have been referred to as 'connectors' or 'adapter adapters.' Murine cytomegalovirus glycoprotein m04/gp34 binds stably to MHC class-I (MHC-I) molecules and suspiciously carries a canonical YXXI broken vertical bar endocytosis motif YRRF in its cytoplasmic tail. Disconnection from AP2 by motif mutation ARRF should retain m04-MHC-I complexes at the cell surface and result in an enhanced silencing of natural killer (NK) cells, which recognize them via inhibitory receptors. We have tested this prediction with a recombinant virus in which the AP2 motif is selectively destroyed by point mutation Y248A, and compared this with the deletion of the complete protein in a Delta m04 mutant. Phenotypes were antithetical in that loss of AP2-binding enhanced NK cell silencing, whereas absence of m04-MHC-I released them from silencing. We thus conclude that AP2-binding antagonizes NK cell silencing by enhancing endocytosis of the inhibitory ligand m04-MHC-I. Based on a screen for tyrosine-based endocytic motifs in cytoplasmic tail sequences, we propose here the new hypothesis that most proteins of the m02-m16 gene family serve as 'adapter adapters,' each selecting its specific cell surface cargo for clathrin-assisted internalization.
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