HVCN1 modulates BCR signal strength via regulation of BCR-dependent generation of reactive oxygen species.
Voltage-gated proton currents regulate generation of reactive oxygen species (ROS) in phagocytic cells. In B cells, stimulation of the B cell antigen receptor (BCR) results in the production of ROS that participate in B cell activation, but the involvement of proton channels is unknown. We report here that the voltage-gated proton channel HVCN1 associated with the BCR complex and was internalized together with the BCR after activation. BCR-induced generation of ROS was lower in HVCN1-deficient B cells, which resulted in attenuated BCR signaling via impaired BCR-dependent oxidation of the tyrosine phosphatase SHP-1. This resulted in less activation of the kinases Syk and Akt, impaired mitochondrial respiration and glycolysis and diminished antibody responses in vivo. Our findings identify unanticipated functions for proton channels in B cells and demonstrate the importance of ROS in BCR signaling and downstream metabolism.
Medical Research Council Toxicology Unit, University of Leicester, Leicester, UK.
Melania
M
Capasso
Mandeep K
MK
Bhamrah
Tom
T
Henley
Robert S
RS
Boyd
Claudia
C
Langlais
Kelvin
K
Cain
David
D
Dinsdale
Karen
K
Pulford
Mahmood
M
Khan
Boris
B
Musset
Vladimir V
VV
Cherny
Deri
D
Morgan
Randy D
RD
Gascoyne
Elena
E
Vigorito
Thomas E
TE
DeCoursey
Ian C M
IC
MacLennan
Martin J S
MJ
Dyer
D000818:Animals; D001402:B-Lymphocytes / Q000201:enzymology / Q000276:immunology*; D004789:Enzyme Activation / Q000276:immunology; D015151:Immunoblotting; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology; D007473:Ion Channels / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000276:immunology; D051058:Oncogene Protein v-akt / Q000276:immunology; D011505:Protein-Tyrosine Kinases / Q000276:immunology; D017382:Reactive Oxygen Species / Q000276:immunology*; D011947:Receptors, Antigen, B-Cell / Q000276:immunology*; D015398:Signal Transduction; D000072377:Syk Kinase
C540876:Hv1 proton channel, mouse; D047908:Intracellular Signaling Peptides and Proteins; D007473:Ion Channels; D017382:Reactive Oxygen Species; D011947:Receptors, Antigen, B-Cell; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D051058:Oncogene Protein v-akt