title: The intertransmembrane region of Kaposi's sarcoma-associated herpesvirus modulator of immune recognition 2 contributes to B7-2 downregulation.
abstract: Kaposi's sarcoma-associated herpesvirus (KSHV), a human tumor virus, encodes two homologous membrane-associated E3 ubiquitin ligases, modulator of immune recognition 1 (MIR1) and MIR2, to evade host immunity. Both MIR1 and MIR2 downregulate the surface expression of major histocompatibility complex class I (MHC I) molecules through ubiquitin-mediated endocytosis followed by lysosomal degradation. Since MIR2 additionally downregulates a costimulatory molecule (B7-2) and an integrin ligand (intercellular adhesion molecule 1 [ICAM-1]), MIR2 is thought to be a more important molecule for immune evasion than MIR1; however, the molecular basis of the MIR2 substrate specificity remains unclear. To address this issue, we determined which regions of B7-2 and MIR2 are required for MIR2-mediated B7-2 downregulation. Experiments with chimeras made by swapping domains between human B7-2 and CD8α, a non-MIR2 substrate, and between MIR1 and MIR2 demonstrated a significant contribution of the juxtamembrane (JM) region of B7-2 and the intertransmembrane (ITM) region of MIR2 to MIR2-mediated downregulation. Structure prediction and mutagenesis analyses indicate that Phe119 and Ser120 in the MIR2 ITM region and Asp244 in the B7-2 JM region contribute to the recognition of B7-2 by MIR2. This finding provides new insight into the molecular basis of substrate recognition by MIR family members.
authors.affiliation: Laboratory for Infectious Immunity, RIKEN Research Center for Allergy and Immunology, Tsurumi-ku, Yokohama, Kanagawa, Japan.
authors.forename: Mizuho
authors.initials: M
authors.lastname: Kajikawa
authors.forename: Pai-Chi
authors.initials: PC
authors.lastname: Li
authors.forename: Eiji
authors.initials: E
authors.lastname: Goto
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Miyashita
authors.forename: Masami
authors.initials: M
authors.lastname: Aoki-Kawasumi
authors.forename: Mari
authors.initials: M
authors.lastname: Mito-Yoshida
authors.forename: Mika
authors.initials: M
authors.lastname: Ikegaya
authors.forename: Yuji
authors.initials: Y
authors.lastname: Sugita
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ishido
mesh_terms: D000596:Amino Acids / Q000737:chemistry; D051940:B7-2 Antigen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D015536:Down-Regulation / Q000276:immunology*; D019288:Herpesvirus 8, Human / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017874:Immediate-Early Proteins
chemical_list: D000596:Amino Acids; D051940:B7-2 Antigen; D014764:Viral Proteins; C405867:K5 protein, Human herpesvirus 8; D017874:Immediate-Early Proteins