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

  • EMBO J. 2021 May 3;40(9):e104888. doi: 10.15252/embj.2020104888.
Evan Nair-Gill  1  2 ,  Massimo Bonora  3 ,  Xue Zhong  1 ,  Aijie Liu  1 ,  Amber Miranda  1 ,  Nathan Stewart  1 ,  Sara Ludwig  1 ,  Jamie Russell  1 ,  Thomas Gallagher  1 ,  Paolo Pinton  3 ,  Bruce Beutler  1
Affiliations
  • 1. Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 2. Division of Rheumatic Diseases, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 3. Department of Medical Sciences, Section of Experimental Medicine, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy.
PMID: 33630350 DOI: 10.15252/embj.2020104888
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.

Keywords
Pacs1; Wdr37; calcium homeostasis; lymphocyte quiescence; lymphoproliferative disease.