AQP8 transports NOX2-generated H2O2 across the plasma membrane to promote signaling in B cells

Milena Bertolotti, Giada Farinelli, Mauro Galli, Alessandro Aiuti, Roberto Sitia

Research output: Contribution to journalArticlepeer-review

Abstract

H2O2 acts as a secondmessenger in key signaling circuits, transientlymodulating tyrosine phosphatases and kinases. We investigated its origin, membrane transport, and functional role during B cell activation and differentiation. Our data identified NADPH-oxidase 2 as the main source of H2O2 and aquaporin 8 as a transport facilitator across the plasmamembrane. On aquaporin 8 silencing, inducible B lymphoma cells responded poorly to TLR and BCR stimulation. Their differentiation was severely impaired, as demonstrated by retarded onset of IgM polymerization, low amounts of IgM secretion, and prolonged BCR expression on the cell surface. A silencing-resistant aquaporin 8 rescued responsiveness, confirming that the import of H2O2 across the membrane is essential for B cell activation. The addition of exogenous catalase to primary B splenocytes severely impaired the tyrosine phosphorylation induced by BCR cross-linking, as did the absence of NOX2 in a murine model of chronic granulomatous disease. Importantly, re-expression of gp91phox through gene therapy restored the specific B cell signaling deficiency in NOX2-/-cells. Thus, efficient induction of B cell activation and differentiation requires intact H2O2 fluxes across the plasma membrane for signal amplification.

Original languageEnglish
Pages (from-to)1071-1079
Number of pages9
JournalJournal of Leukocyte Biology
Volume100
Issue number5
DOIs
Publication statusPublished - Nov 1 2016

Keywords

  • Aquaporins
  • Differentiation
  • Immunoglobulin
  • Redox

ASJC Scopus subject areas

  • Immunology
  • Cell Biology

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