Differential but competitive binding of Nogo protein and class I major histocompatibility complex (MHCI) to the PIR-B ectodomain provides an inhibition of cells

Haruka Matsushita, Shota Endo, Eiji Kobayashi, Yuzuru Sakamoto, Keisuke Kobayashi, Kohji Kitaguchi, Kimiko Kuroki, Arvid Söderhäll, Katsumi Maenaka, Akira Nakamura, Stephen M. Strittmatter, Toshiyuki Takai

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Binding of class I MHC molecules (MHCI) to an inhibitory receptor, PIR-B, expressed on B cells and myeloid cells provides constitutive cellular inhibition, thus ensuring peripheral tolerance. Recent unexpected findings pointed to a novel inhibitory role of PIR- Binneuriteregenerationthroughbindingtothreeaxonaloutgrowth inhibitors of myelin, including Nogo. Thus, it becomes interesting to determine whether the actions of the inhibitory myelin proteins and MHCI could coexist independently or be mutually exclusive as to the PIR-B-mediated immune and neural cell inhibition. Here, we present data supporting the competition of Nogo- and MHCI-mediated inhibition where they coexist. Kinetic analyses of Nogo and MHCI binding to the whole or a part of the recombinant PIR-B ectodomain revealed that PIR-B binds with higher affinity to Nogo than MHCI and that the MHCI binding only occurred with the N-terminal domains of PIR-B, whereas Nogo binding occurred with either the N- or C-terminal ectodomains. Importantly, kinetic tests indicated that the binding to PIR-B of Nogo and MHCI was competitive. Both endogenous and exogenous Nogo intensified the PIR-B-mediated suppression of interleukin-6 release from lipopolysaccharide-stimulated wildtype, but not PIR-B-deficient, cultured mast cells, indicating that PIR-B mediates Nogo-induced inhibition. Thus, we propose a novel mechanism by which PIR-B-mediated regulation is achieved differentially but competitively via MHCI and Nogo in cells of the immune system.

Original languageEnglish
Pages (from-to)25739-25747
Number of pages9
JournalJournal of Biological Chemistry
Volume286
Issue number29
DOIs
Publication statusPublished - 2011 Jul 22

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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