c-MIR, a human E3 ubiquitin ligase, is a functional homolog of herpesvirus proteins MIR1 and MIR2 and has similar activity.
Kaposi's sarcoma associated-herpes virus encodes two proteins, MIR (modulator of immune recognition) 1 and 2, which are involved in the evasion of host immunity. MIR1 and 2 have been shown to function as an E3 ubiquitin ligase for immune recognition-related molecules (e.g. major histocompatibility complex class I, B7-2, and ICAM-1) through the BKS (bovine herpesvirus 4, Kaposi's sarcoma associated-herpes virus, and Swinepox virus) subclass of plant homeodomain (PHD) domain, termed the BKS-PHD domain. Here we show that the human genome also encodes a novel BKS-PHD domain-containing protein that functions as an E3 ubiquitin ligase and whose putative substrate is the B7-2 co-stimulatory molecule. This novel E3 ubiquitin ligase was designated as c-MIR (cellular MIR) based on its functional and structural similarity to MIR1 and 2. Forced expression of c-MIR induced specific down-regulation of B7-2 surface expression through ubiquitination, rapid endocytosis, and lysosomal degradation of the target molecule. This specific targeting was dependent upon the binding of c-MIR to B7-2. Replacing the BKS-PHD domain of MIR1 with the corresponding domain of c-MIR did not alter MIR1 function. The discovery of c-MIR, a novel E3 ubiquitin ligase, highlights the possibility that viral immune regulatory proteins originated in the host genome and presents unique functions of BKS-PHD domain-containing proteins in mammals.
Goto
Eiji
E
Division of Microbiology, Department of Genome Sciences, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017, Japan.
Ishido
Satoshi
S
Sato
Yuya
Y
Ohgimoto
Shinji
S
Ohgimoto
Kaori
K
Nagano-Fujii
Motoko
M
Hotta
Hak
H
D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000378:metabolism*; D051940:B7-2 Antigen; D003713:Dendritic Cells / Q000201:enzymology; D015536:Down-Regulation; D004705:Endocytosis; D006801:Humans; D008025:Ligases / Q000737:chemistry / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D044767:Ubiquitin-Protein Ligases; D014452:Ubiquitins / Q000378:metabolism; D014764:Viral Proteins; D017874:Immediate-Early Proteins
D015703:Antigens, CD; D051940:B7-2 Antigen; D008025:Ligases; D008562:Membrane Glycoproteins; D044767:Ubiquitin-Protein Ligases; D014452:Ubiquitins; D014764:Viral Proteins; C497964:CD86 protein, human; C405867:K5 protein, Human herpesvirus 8; D017874:Immediate-Early Proteins