The Deubiquitylase Otub1 Regulates the Chemotactic Response of Splenic B Cells by Modulating the Stability of the γ-Subunit Gng2.

Autor: Luo VM; Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada.; Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Québec, Canada., Shen C; Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada.; McGill Research Centre for Complex Traits, McGill University, Montréal, Québec, Canada., Worme S; Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Québec, Canada.; Division of Experimental Medicine, McGill University, Montréal, Québec, Canada., Bhagrath A; McGill Research Centre for Complex Traits, McGill University, Montréal, Québec, Canada.; Department of Physiology, McGill University, Montréal, Québec, Canada., Simo-Cheyou E; Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada., Findlay S; Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Québec, Canada.; Division of Experimental Medicine, McGill University, Montréal, Québec, Canada., Hébert S; Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Québec, Canada.; Department of Human Genetics, McGill University, Montréal, Québec, Canada., Wai Lam Poon W; Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Québec, Canada.; Division of Experimental Medicine, McGill University, Montréal, Québec, Canada., Aryanpour Z; Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Québec, Canada., Zhang T; Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Québec, Canada., Zahedi RP; Manitoba Centre for Proteomics & Systems Biology, University of Manitoba, Winnipeg, Manitoba, Canada.; Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.; Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada.; CancerCare Manitoba Research Institute, Winnipeg, Manitoba, Canada., Boulais J; Institut de Recherches Cliniques de Montréal (IRCM), Montreal, Québec, Canada., Buchwald ZS; Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA., Borchers CH; Segal Cancer Proteomics Centre, Lady Davis Institute for Medical Research, McGill University, Montréal, Québec, Canada.; Gerald Bronfman Department of Oncology, Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Québec, Canada.; Department of Pathology, McGill University, Montreal, Québec, Canada., Côté JF; Institut de Recherches Cliniques de Montréal (IRCM), Montreal, Québec, Canada.; Department of Anatomy and Cell Biology, McGill University, Montreal, Québec, Canada.; Département de Biochimie et Médecine Moléculaire, Université de Montréal, Montreal, Québec, Canada.; Département de Médecine (Programmes de Biologie Moléculaire), Université de Montréal, Montreal, Québec, Canada., Kleinman CL; Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Québec, Canada.; Department of Human Genetics, McGill University, Montréal, Québec, Canada., Mandl JN; Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada.; McGill Research Centre for Complex Traits, McGill University, Montréal, Québec, Canada.; Department of Physiology, McGill University, Montréal, Québec, Canada., Orthwein A; Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada.; Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Québec, Canada.; Division of Experimental Medicine, McGill University, Montréal, Québec, Canada.; Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA.; Gerald Bronfman Department of Oncology, Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Québec, Canada.
Jazyk: angličtina
Zdroj: Molecular and cellular biology [Mol Cell Biol] 2024 Jan; Vol. 44 (1), pp. 1-16. Date of Electronic Publication: 2024 Jan 29.
DOI: 10.1080/10985549.2023.2290434
Abstrakt: The ubiquitin proteasome system performs the covalent attachment of lysine 48-linked polyubiquitin chains to substrate proteins, thereby targeting them for degradation, while deubiquitylating enzymes (DUBs) reverse this process. This posttranslational modification regulates key features both of innate and adaptative immunity, including antigen presentation, protein homeostasis and signal transduction. Here we show that loss of one of the most highly expressed DUBs, Otub1, results in changes in murine splenic B cell subsets, leading to a significant increase in marginal zone and transitional B cells and a concomitant decrease in follicular B cells. We demonstrate that Otub1 interacts with the γ-subunit of the heterotrimeric G protein, Gng2, and modulates its ubiquitylation status, thereby controlling Gng2 stability. Proximal mapping of Gng2 revealed an enrichment in partners associated with chemokine signaling, actin cytoskeleton and cell migration. In line with these findings, we show that Otub1 -deficient B cells exhibit greater Ca 2+ mobilization, F-actin polymerization and chemotactic responsiveness to Cxcl12, Cxcl13 and S1P in vitro , which manifests in vivo as altered localization of B cells within the spleen. Together, our data establishes Otub1 as a novel regulator of G-protein coupled receptor signaling in B cells, regulating their differentiation and positioning in the spleen.
Databáze: MEDLINE