Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) activity is required for V(D)J recombination. Academic Article uri icon

Overview

abstract

  • 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.

publication date

  • May 25, 2021

Research

keywords

  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • V(D)J Recombination

Identity

PubMed Central ID

  • PMC8155808

Scopus Document Identifier

  • 85106922771

Digital Object Identifier (DOI)

  • 10.1016/j.celrep.2019.04.011

PubMed ID

  • 34033676

Additional Document Info

volume

  • 218

issue

  • 8