CCDC88B interacts with RASAL3 and ARHGEF2 and regulates dendritic cell function in neuroinflammation and colitis

• Published in: Communications biology Vol. 7; no. 1; p. 77
• Main Authors: Olivier, Jean-Frederic, Langlais, David, Jeyakumar, Thiviya, Polyak, Maria J., Galarneau, Luc, Cayrol, Romain, Jiang, Hua, Molloy, Kelly R., Xu, Guoyue, Suzuki, Harumi, LaCava, John, Gros, Philippe, Fodil, Nassima
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.01.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/31; 13/51; 14/35; 38/43; 45/70; 631/250/256; 631/337/475/2290; 631/80/84; 64/60; 692/699/1503/257; 82/58; 82/81; Animals; Biomedical and Life Sciences; Cell Physiological Phenomena; Chromosome 1; Colitis; Colitis - genetics; Cytoskeleton; Dendritic Cells; Gene mapping; Guanine nucleotide exchange factor; Humans; Inflammatory bowel disease; Inflammatory diseases; Life Sciences; Mice; Molecular modelling; Motility; Neuroinflammatory Diseases; Proteins; Ras protein; Rho Guanine Nucleotide Exchange Factors - genetics; RhoA protein; Risk factors
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-023-05751-9

CCDC88B is a risk factor for several chronic inflammatory diseases in humans and its inactivation causes a migratory defect in DCs in mice. CCDC88B belongs to a family of cytoskeleton-associated scaffold proteins that feature protein:protein interaction domains. Here, we identified the Rho/Rac Guanine Nucleotide Exchange Factor 2 (ARHGEF2) and the RAS Protein Activator Like 3 (RASAL3) as CCDC88B physical and functional interactors. Mice defective in Arhgef2 or Rasal3 show dampened neuroinflammation, and display altered cellular response and susceptibility to colitis; ARHGEF2 maps to a human Chromosome 1 locus associated with susceptibility to IBD. Arhgef2 and Rasal3 mutant DCs show altered migration and motility in vitro, causing either reduced ( Arhgef2 ) or enhanced ( Rasal3 ) migratory properties. The CCDC88B/RASAL3/ARHGEF2 complex appears to regulate DCs migration by modulating activation of RHOA, with ARHGEF2 and RASAL3 acting in opposite regulatory fashions, providing a molecular mechanism for the involvement of these proteins in DCs immune functions. CCDC88B physically interacts with ARHGEF2 and RASAL3; defective mice show dampened neuroinflammation, altered susceptibility to colitis and altered DCs motility by modulating RHOA, with ARHGEF2 and RASAL3 acting in opposite regulatory fashions.