期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 218, 期 8, 页码 -出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20201708
关键词
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资金
- National Institutes of Health [R01 AI047829, R01 AI074953, R01 DK097441, R01 CA95641, R01 AI 032524, R37 NS036942]
- Leukemia & Lymphoma Society Career Development Program Fellowship
- Vetenskapsr adet
- Svenska Sallskapet forr Medicinsk Forskning
- Tore Nilssons Stiftelse
- Jeanssons Stiftelser
- Hudfonden
- ALF Medicin Stockholm
SERCA proteins modulate intracellular Ca2+ levels to regulate RAG1 and RAG2 gene expression and V(D)J recombination, and defects in SERCA functions cause lymphopenia.
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.
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