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

• Published in: Molecular and cellular biology Vol. 44; no. 1; pp. 1 - 16
• Main Authors: Luo, Vincent M, Shen, Connie, Worme, Samantha, Bhagrath, Aanya, Simo-Cheyou, Estelle, Findlay, Steven, Hébert, Steven, Wai Lam Poon, William, Aryanpour, Zahra, Zhang, Thomas, Zahedi, René P, Boulais, Jonathan, Buchwald, Zachary S, Borchers, Christoph H, Côté, Jean-Francois, Kleinman, Claudia L, Mandl, Judith N, Orthwein, Alexandre
• Format: Journal Article
• Language: English
• Published: United States 2024
• Subjects: Animals; B-Lymphocytes - metabolism; Chemotaxis, Leukocyte - genetics; Cysteine Endopeptidases - metabolism; Deubiquitinating Enzymes - metabolism; GTP-Binding Proteins - metabolism; Mice; Proteasome Endopeptidase Complex - metabolism; Signal Transduction; Spleen - metabolism; Ubiquitin - metabolism; Ubiquitination; B cell; Deubiquitylase; spleen; marginal zone; heterotrimeric G protein gamma subunit 2 (γ-subunit); chemokine receptor; deubiquitylation; chemotaxis
• ISSN: 1098-5549; 1098-5549
• DOI: 10.1080/10985549.2023.2290434

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
-deficient B cells exhibit greater Ca
mobilization, F-actin polymerization and chemotactic responsiveness to Cxcl12, Cxcl13 and S1P
, which manifests
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.