BCALM (AC099524.1) Is a Human B Lymphocyte–Specific Long Noncoding RNA That Modulates B Cell Receptor–Mediated Calcium Signaling
Year: 2020
Type: article
Abstract: Of the thousands of long noncoding RNAs (lncRNA) identified in lymphocytes, very few have defined functions. In this study, we report the discovery and functional elucidation of a human B cell–specific lncRNA with high levels of expression in three types of B cell cancer and normal B cells. The AC099524.1 gene is upstream of the gene encoding the B cell–specific phospholipase C γ 2 (PLCG2), a B cell–specific enzyme that stimulates intracellular Ca2+ signaling in response to BCR activation. AC099524.1 (B cell–associated lncRNA modulator of BCR-mediated Ca+ signaling [BCALM]) transcripts are localized in the cytoplasm and, as expected, CRISPR/Cas9 knockout of AC099524.1 did not affect PLCG2 mRNA or protein expression. lncRNA interactome, RNA immunoprecipitation, and coimmunoprecipitation studies identified BCALM-interacting proteins in B cells, including phospholipase D 1 (PLD1), and kinase adaptor proteins AKAP9 (AKAP450) and AKAP13 (AKAP-Lbc). These two AKAP proteins form signaling complexes containing protein kinases A and C, which phosphorylate and activate PLD1 to produce phosphatidic acid (PA). BCR stimulation of BCALM-deficient B cells resulted in decreased PLD1 phosphorylation and increased intracellular Ca+ flux relative to wild-type cells. These results suggest that BCALM promotes negative feedback that downmodulates BCR-mediated Ca+ signaling by promoting phosphorylation of PLD1 by AKAP-associated kinases, enhancing production of PA. PA activates SHP-1, which negatively regulates BCR signaling. We propose the name BCALM for B-Cell Associated LncRNA Modulator of BCR-mediated Ca+ signaling. Our findings suggest a new, to our knowledge, paradigm for lncRNA-mediated modulation of lymphocyte activation and signaling, with implications for B cell immune response and BCR-dependent cancers.
Source: The Journal of Immunology
Authors: Sarah C Pyfrom, Chaz C Quinn, Hannah K Dorando, Hong Luo, Jacqueline E Payton
Institution: Washington University in St. Louis
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: bronze
Funders: Institute of Clinical and Translational Sciences, Alvin J. Siteman Cancer Center, Georgia Clinical and Translational Science Alliance, National Institutes of Health, National Cancer Institute, National Institute of General Medical Sciences, National Center for Research Resources, National Center for Advancing Translational Sciences
Awards: G1114310655, G1278655010, G1485266116, G1661677298, G1699415014, G2052854178, G2195970601, G245842400, G299873027, G3455473179, G4142786993, G4241677154, TARGETING EPIGENOMIC SIGNATURES IN NON-HODGKIN LYMPHOMA FOR NOVEL THERAPEUTICS, G611383016, G6120206497, Washington University Institute of Clinical and Translational Sciences, SEQUENCE-SPECIFIC CHROMATIN MODIFIERS; NOVEL PROTEIN THERAPEUTICS FOR B CELL LYMPHOMA, G7647900390, National Research Service Award-Medical Scientist, G8242737674, G9000006824, G9000115080, G9000319192, Washington University Institute of Clinical and Translational Sciences, Cancer Center Support Grant
OpenAlex ID: W3036889400