A whole-genome CRISPR/Cas9 screen identified ATP2A2, the gene encoding the Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) 2 protein, as being important for V(D)J recombination. SERCAs are ER transmembrane proteins that pump Ca2+ from the cytosol into the ER lumen to maintain the ER Ca2+ reservoir and regulate cytosolic Ca2+-dependent processes. In preB cells, loss of SERCA2 leads to reduced V(D)J recombination kinetics due to diminished RAG-mediated DNA cleavage. SERCA2 deficiency in B cells leads to increased expression of SERCA3, and combined loss of SERCA2 and SERCA3 results in decreased ER Ca2+ levels, increased cytosolic Ca2+ levels, reduction in RAG1 and RAG2 gene expression, and a profound block in V(D)J recombination. Mice with B cells deficient in SERCA2 and humans with Darier disease, caused by heterozygous ATP2A2 mutations, have reduced numbers of mature B cells. We conclude that SERCA proteins modulate intracellular Ca2+ levels to regulate RAG1 and RAG2 gene expression and V(D)J recombination and that defects in SERCA functions cause lymphopenia.
Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) activity is required for V(D)J recombination
Disclosures: The authors declare no competing interests exist.
C.-C. Chen’s present address is Massachusetts Institute of Technology, Boston, MA.
J. de Juan-Sanz’s present address is Sorbonne Université, Institut du Cerveau–Paris Brain Institute, Institut national de la santé et de la recherche médicale, Centre national de la recherche scientifique, Assistance Publique–Hôpitaux de Paris, Hôpital de la Pitié Salpêtrière, Paris, France.
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Chun-Chin Chen, Bo-Ruei Chen, Yinan Wang, Philip Curman, Helen A. Beilinson, Ryan M. Brecht, Catherine C. Liu, Ryan J. Farrell, Jaime de Juan-Sanz, Louis-Marie Charbonnier, Shingo Kajimura, Timothy A. Ryan, David G. Schatz, Talal A. Chatila, Jakob D. Wikstrom, Jessica K. Tyler, Barry P. Sleckman; Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) activity is required for V(D)J recombination. J Exp Med 2 August 2021; 218 (8): e20201708. doi: https://doi.org/10.1084/jem.20201708
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