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

Jean-Frederic Olivier; David Langlais; Thiviya Jeyakumar; Maria J Polyak; Luc Galarneau; Romain Cayrol; Hua Jiang; Kelly R Molloy; Guoyue Xu; Harumi Suzuki; John LaCava; Philippe Gros; Nassima Fodil

doi:10.1038/s42003-023-05751-9

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

Commun Biol. 2024 Jan 10;7(1):77. doi: 10.1038/s42003-023-05751-9.

Authors

Jean-Frederic Olivier^#^{1

2}, David Langlais^#^{2

3}, Thiviya Jeyakumar^{1

2}, Maria J Polyak^{1

2}, Luc Galarneau⁴, Romain Cayrol^{5

6

7}, Hua Jiang⁸, Kelly R Molloy⁹, Guoyue Xu³, Harumi Suzuki¹⁰, John LaCava^{8

11}, Philippe Gros^{12

13}, Nassima Fodil^{2

14}

Affiliations

¹ Department of Biochemistry, McGill University, Montreal, QC, Canada.
² McGill Research Center on Complex Traits, Montreal, QC, Canada.
³ Department of Human Genetics, Victor Phillip Dahdaleh Institute of Genomic Medicine, Montreal, QC, Canada.
⁴ Department of Medicine, Sherbrooke University, Sherbrooke, QC, Canada.
⁵ Department of Pathology, University of Montreal Hospital Center (CHUM), Montreal, QC, Canada.
⁶ University of Montreal Hospital Center Research Center (CR-CHUM), Montreal, QC, Canada.
⁷ Department of Pathology and Cellular Biology, University of Montreal, Montreal, QC, Canada.
⁸ Laboratory of Cellular and Structural Biology, The Rockefeller University, New York, NY, USA.
⁹ Laboratory of Mass Spectrometry and Gaseous Ion Chemistry, The Rockefeller University, New York, NY, USA.
¹⁰ Department of Immunology and Pathology, National Center for Global Health and Medicine, Tokyo, Japan.
¹¹ European Research Institute for the Biology of Ageing, University Medical Center Groningen, Groningen, The Netherlands.
¹² Department of Biochemistry, McGill University, Montreal, QC, Canada. philippe.gros@mcgill.ca.
¹³ McGill Research Center on Complex Traits, Montreal, QC, Canada. philippe.gros@mcgill.ca.
¹⁴ CERMO-FC, Pavillon des Sciences Biologiques, Montreal, QC, Canada.

^# Contributed equally.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Cell Physiological Phenomena
Colitis* / genetics
Cytoskeleton
Dendritic Cells
Humans
Mice
Neuroinflammatory Diseases*
Rho Guanine Nucleotide Exchange Factors / genetics

Substances

ARHGEF2 protein, human
Rho Guanine Nucleotide Exchange Factors
RASAL3 protein, mouse
Arhgef2 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding