TIFAB regulates the TIFA-TRAF6 signaling pathway involved in innate immunity by forming a heterodimer complex with TIFA

• 成果类型: Article
• 署名作者: Nakamura, Teruya; Ohyama, Chiaki; Sakamoto, Madoka; Toma, Tsugumasa; Tateishi, Hiroshi; Matsuo, Mihoko; Chirifu, Mami; Ikemizu, Shinji; Morioka, Hiroshi; Fujita, Mikako; Inoue, Jun- ichiro; Yamagata, Yuriko
• 署名单位: Kumamoto University; Kumamoto University; University of Tokyo
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12837
• DOI: 10.1073/pnas.2318794121
• 发表日期: 2024-03-12
• 关键词: traf-interacting protein; nf-kappa-b; domain; mechanism; oligomerization; identification; hematopoiesis; binding; fha

摘要

Nuclear factor KB (NF -KB) is activated by various inflammatory and infectious molecules and is involved in immune responses. It has been elucidated that ADP-(3-D- manno- heptose (ADP-Hep), a metabolite in gram- negative bacteria, activates NF -KB through alpha- kinase 1 (ALPK1)-TIFA-TRAF6 signaling. ADP-Hep stimulates the kinase activity of ALPK1 for TIFA phosphorylation. Complex formation between phosphorylation- dependent TIFA oligomer and TRAF6 promotes the polyubiquitination of TRAF6 for NF -KB activation. TIFAB, a TIFA homolog lacking a phosphorylation site and a TRAF6 binding motif, is a negative regulator of TIFA-TRAF6 signaling and is implicated in myeloid diseases. TIFAB is indicated to regulate TIFA-TRAF6 signaling through interactions with TIFA and TRAF6; however, little is known about its biological function. We demonstrated that TIFAB forms a complex not with the TIFA dimer, an intrinsic form of TIFA involved in NF -KB activation, but with monomeric TIFA. The structural analysis of the TIFA/TIFAB complex and the biochemical and cell - based analyses showed that TIFAB forms a stable heterodimer with TIFA, inhibits TIFA dimer formation, and suppresses TIFA-TRAF6 signaling. The resultant TIFA/TIFAB complex is a pseudo-TIFA dimer lacking the phosphorylation site and TRAF6 binding motif in TIFAB and cannot form the orderly structure as proposed for the phosphorylated TIFA oligomer involved in NF -KB activation. This study elucidated the molecular and structural basis for the regulation of TIFA-TRAF6 signaling by TIFAB.