title: Enhanced activation of an amino-terminally truncated isoform of the voltage-gated proton channel HVCN1 enriched in malignant B cells.
abstract: HVCN1 (Hydrogen voltage-gated channel 1) is the only mammalian voltage-gated proton channel. In human B lymphocytes, HVCN1 associates with the B-cell receptor (BCR) and is required for optimal BCR signaling and redox control. HVCN1 is expressed in malignant B cells that rely on BCR signaling, such as chronic lymphocytic leukemia (CLL) cells. However, little is known about its regulation in these cells. We found that HVCN1 was expressed in B cells as two protein isoforms. The shorter isoform (HVCN1S) was enriched in B cells from a cohort of 76 CLL patients. When overexpressed in a B-cell lymphoma line, HVCN1S responded more profoundly to protein kinase C-dependent phosphorylation. This more potent enhanced gating response was mediated by increased phosphorylation of the same residue responsible for enhanced gating in HVCN1L, Thr(29). Furthermore, the association of HVCN1S with the BCR was weaker, which resulted in its diminished internalization upon BCR stimulation. Finally, HVCN1S conferred a proliferative and migratory advantage as well as enhanced BCR-dependent signaling. Overall, our data show for the first time, to our knowledge, the existence of a shorter isoform of HVCN1 with enhanced gating that is specifically enriched in malignant B cells. The properties of HVCN1S suggest that it may contribute to the pathogenesis of BCR-dependent B-cell malignancies.
authors.affiliation: Centre for Cancer and Inflammation, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, United Kingdom;
authors.forename: Elayne
authors.initials: E
authors.lastname: Hondares
authors.affiliation: Centre for Cancer and Inflammation, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, United Kingdom;
authors.forename: Mark Adrian
authors.initials: MA
authors.lastname: Brown
authors.affiliation: ICS-4 Forschungszentrum Jülich, 52425 Jülich, Germany;
authors.forename: Boris
authors.initials: B
authors.lastname: Musset
authors.affiliation: Department of Molecular Biophysics and Physiology, Rush University, Chicago, IL 60612;
authors.forename: Deri
authors.initials: D
authors.lastname: Morgan
authors.affiliation: Department of Molecular Biophysics and Physiology, Rush University, Chicago, IL 60612;
authors.forename: Vladimir V
authors.initials: VV
authors.lastname: Cherny
authors.affiliation: Centre for Cancer and Inflammation, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, United Kingdom;
authors.forename: Christina
authors.initials: C
authors.lastname: Taubert
authors.affiliation: Medical Research Council Toxicology Unit, Leicester LE1 9HN, United Kingdom;
authors.forename: Mandeep K
authors.initials: MK
authors.lastname: Bhamrah
authors.affiliation: Centre for Biochemical Pharmacology, William Harvey Research Institute, Queen Mary University of London, London EC1M 6BQ, United Kingdom;
authors.forename: David
authors.initials: D
authors.lastname: Coe
authors.affiliation: Centre for Biochemical Pharmacology, William Harvey Research Institute, Queen Mary University of London, London EC1M 6BQ, United Kingdom;
authors.forename: Federica
authors.initials: F
authors.lastname: Marelli-Berg
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, United Kingdom; and.
authors.forename: John G
authors.initials: JG
authors.lastname: Gribben
authors.affiliation: Ernest and Helen Scott Haematological Research Institute, University of Leicester, Leicester LE1 9HN, United Kingdom.
authors.forename: Martin J S
authors.initials: MJ
authors.lastname: Dyer
authors.affiliation: Department of Molecular Biophysics and Physiology, Rush University, Chicago, IL 60612; tdecours@rush.edu m.capasso@qmul.ac.uk.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: DeCoursey
authors.affiliation: Centre for Cancer and Inflammation, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, United Kingdom; tdecours@rush.edu m.capasso@qmul.ac.uk.
authors.forename: Melania
authors.initials: M
authors.lastname: Capasso
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D019337:Hematologic Neoplasms / Q000276:immunology*; D006801:Humans; D007473:Ion Channels / Q000378:metabolism*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology*; D051379:Mice; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C510235:HVCN1 protein, human; D007473:Ion Channels; D020033:Protein Isoforms; D017382:Reactive Oxygen Species; D011493:Protein Kinase C
keywords: Hv1; chronic lymphocytic leukemia; gating kinetics; phosphorylation; proton currents