Calcium flux control by Pacs1‐Wdr37 promotes lymphocyte quiescence and lymphoproliferative diseases. (25th February 2021)

• Record Type: Journal Article
• Authors: Nair‐Gill, Evan; Bonora, Massimo; Zhong, Xue; Liu, Aijie; Miranda, Amber; Stewart, Nathan; Ludwig, Sara; Russell, Jamie; Gallagher, Thomas; Pinton, Paolo; Beutler, Bruce
• Is Part Of: EMBO journal. Volume 40:Number 9(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-02-25
• Subjects: calcium homeostasis -- lymphocyte quiescence -- lymphoproliferative disease -- Pacs1 -- Wdr37; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.2020104888
• Languages: English
• ISSNs: 0261-4189

Abstract

Abstract: Endoplasmic reticulum (ER) calcium (Ca 2+ ) 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 Ca 2+ handling in lymphocytes. Deletion of Pacs1 or Wdr37 caused peripheral lymphopenia that was linked to blunted Ca 2+ 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 Ca 2+ handling and presents a new target for lymphoproliferative disease therapy. SYNOPSIS: Pacs1‐Wdr37 form a complex that maintains ER Ca 2+ homeostasis. Disrupting Pacs1‐Wdr37 decreases lymphocyte quiescence causing lymphocyte deficiency and suppression of lymphoproliferative diseases. Deletion of Pacs1 or Wdr37 impairs lymphocyte Ca 2+ flux after antigen receptor stimulation. Pacs1 and Wdr37 bind and stabilize each other in vivo . Pacs1 deletion suppresses ER Ca 2+ release by limiting IP3R expression. Pacs1 deletion increases ER stress, mitochondrial oxygen consumption, and ROS. Abstract : A forward generic screen identifies the Pacs1‐Wdr37 complex as being required for controlled endoplasmic reticulum Ca 2+ handling, and in turn for lymphocyte development and survival in mice.