Calcium flux control by Pacs1-Wdr37 promotes lymphocyte quiescence and lymphoproliferative diseases

Evan Nair-Gill, Massimo Bonora, Xue Zhong, Aijie Liu, Amber Miranda, Nathan Stewart, Sara Ludwig, Jamie Russell, Thomas Gallagher, Paolo Pinton, Bruce Beutler

Research output: Contribution to journalArticlepeer-review

Abstract

Endoplasmic reticulum (ER) calcium (Ca2+) stores are critical to proteostasis, intracellular signaling, and cellular bioenergetics. Through forward genetic screening in mice, we identified two members of a new complex, Pacs1 and Wdr37, which are required for normal ER Ca2+ handling in lymphocytes. Deletion of Pacs1 or Wdr37 caused peripheral lymphopenia that was linked to blunted Ca2+ release from the ER after antigen receptor stimulation. Pacs1-deficient cells showed diminished inositol triphosphate receptor expression together with increased ER and oxidative stress. Mature Pacs1−/− B cells proliferated and died in vivo under lymphocyte replete conditions, indicating spontaneous loss of cellular quiescence. Disruption of Pacs1-Wdr37 did not diminish adaptive immune responses, but potently suppressed lymphoproliferative disease models by forcing loss of quiescence. Thus, Pacs1-Wdr37 plays a critical role in stabilizing lymphocyte populations through ER Ca2+ handling and presents a new target for lymphoproliferative disease therapy.

Original languageEnglish (US)
Article numbere104888
JournalEMBO Journal
Volume40
Issue number9
DOIs
StatePublished - May 3 2021

Keywords

  • Pacs1
  • Wdr37
  • calcium homeostasis
  • lymphocyte quiescence
  • lymphoproliferative disease

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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