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The deubiquitylase Otub1 regulates the chemotactic response in splenic B cells by modulating the stability of the g-subunit Gng2

ABSTRACT: The ubiquitin (Ub) proteasome system (UPS) performs the covalent attachment of lysine 48-linked poly-Ub chains to substrate proteins, thereby targeting them for degradation, while deubiquitylating enzymes (DUBs) reverse this process. This post-translational modification system regulates many processes in the innate and adaptive immune system. Here we show that loss of one of the most highly expressed DUBs, Otub1, results in changes in splenic B cell subsets, leading to a significant increase in marginal zone and transitional B cells and a decrease in follicular B cells. We demonstrate that Otub1 interacts with and modulates the ubiquitylation status of the heterotrimeric G-protein g-subunit Gng2, thereby regulating Gng2 stability. Proximal mapping of Gng2 revealed an enrichment in partners associated with cell migration and chemokine signaling. Indeed, Otub1-deficient B cells exhibited sustained chemokine receptor signaling and increased chemokine responsiveness towards Cxcl12, Cxcl13 and S1P in vitro, which manifested in vivo as a defect in the localization of splenic B cells. Together, our data establishes Otub1 as a novel regulator of G-protein coupled receptor signaling (GPCR) in B cells, altering their positioning and differentiation.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Alexandre Orthwein

PROVIDER: MSV000091229 | MassIVE | Wed Feb 08 12:26:00 GMT 2023

REPOSITORIES: MassIVE

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