生物
细胞生物学
异三聚体G蛋白
信号转导
泛素连接酶
趋化性
蛋白质亚单位
泛素
G蛋白
受体
生物化学
基因
作者
Vincent Luo,Connie Shen,Samantha Worme,Aanya Bhagrath,Estelle R. Simo‐Cheyou,Steven Findlay,Steven C. Hebert,William Wai Lam Poon,Zahra Aryanpour,T. Zhang,René P. Zahedi,Jonathan Boulais,Zachary S. Buchwald,Christoph H. Borchers,Jean‐François Côté,Claudia L. Kleinman,Judith N. Mandl,Alexandre Orthwein
标识
DOI:10.1080/10985549.2023.2290434
摘要
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 Ca2+ 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.
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