Contribution of lysine 11-linked ubiquitination to MIR2-mediated major histocompatibility complex class I internalization.
The polyubiquitin chain is generated by the sequential addition of ubiquitin moieties to target molecules, a reaction between specific lysine residues that is catalyzed by E3 ubiquitin ligase. The Lys(48)-linked and Lys(63)-linked polyubiquitin chains are well established inducers of proteasome-dependent degradation and signal transduction, respectively. The concept has recently emerged that polyubiquitin chain-mediated regulation is even more complex because various types of atypical polyubiquitin chains have been discovered in vivo. Here, we demonstrate that a novel complex ubiquitin chain functions as an internalization signal for major histocompatibility complex class I (MHC I) membrane proteins in vivo. Using a tetracycline-inducible expression system and quantitative mass spectrometry, we show that the polyubiquitin chain generated by the viral E3 ubiquitin ligase of Kaposi sarcoma-associated herpesvirus, MIR2, is a Lys(11) and Lys(63) mixed-linkage chain. This novel ubiquitin chain can function as an internalization signal for MHC I through its association with epsin1, an adaptor molecule containing ubiquitin-interacting motifs.
Goto
Eiji
E
Laboratory for Infectious Immunity, RIKEN Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
Yamanaka
Yuko
Y
Ishikawa
Akiyo
A
Aoki-Kawasumi
Masami
M
Mito-Yoshida
Mari
M
Ohmura-Hoshino
Mari
M
Matsuki
Yohei
Y
Kajikawa
Mizuho
M
Hirano
Hisashi
H
Ishido
Satoshi
S
D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D016827:CD8 Antigens / Q000235:genetics / Q000378:metabolism; D002966:Clathrin / Q000235:genetics / Q000378:metabolism; D004705:Endocytosis; D005434:Flow Cytometry; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D013058:Mass Spectrometry; D008856:Microscopy, Fluorescence; D034622:RNA Interference; D054875:Ubiquitination; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D017874:Immediate-Early Proteins
D033942:Adaptor Proteins, Vesicular Transport; D016827:CD8 Antigens; D002966:Clathrin; D049452:Green Fluorescent Proteins; D015395:Histocompatibility Antigens Class I; D008239:Lysine; D014452:Ubiquitins; D014764:Viral Proteins; C114154:epsin; C405867:K5 protein, Human herpesvirus 8; D017874:Immediate-Early Proteins