Calcium flux control by Pacs1‐Wdr37 promotes lymphocyte quiescence and lymphoproliferative diseases
- 25 February 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in The EMBO Journal
- Vol. 40 (9), e104888
- https://doi.org/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.Funding Information
- National Institutes of Health (R01 AI125581, U19 AI100627)
- Lyda Hill Foundation
- Rheumatology Research Foundation
This publication has 63 references indexed in Scilit:
- Recurrent De Novo Mutations in PACS1 Cause Defective Cranial-Neural-Crest Migration and Define a Recognizable Intellectual-Disability SyndromeAmerican Journal of Human Genetics, 2012
- A dynamic T cell–limited checkpoint regulates affinity-dependent B cell entry into the germinal centerThe Journal of Experimental Medicine, 2011
- IP3 Receptors: Toward Understanding Their ActivationCold Spring Harbor Perspectives in Biology, 2010
- Essential Regulation of Cell Bioenergetics by Constitutive InsP3 Receptor Ca2+ Transfer to MitochondriaCell, 2010
- Ca2+ transfer from the ER to mitochondria: When, how and whyBiochimica et Biophysica Acta (BBA) - Bioenergetics, 2009
- PI3 Kinase Signals BCR-Dependent Mature B Cell SurvivalCell, 2009
- The BH4 domain of Bcl-2 inhibits ER calcium release and apoptosis by binding the regulatory and coupling domain of the IP3 receptorProceedings of the National Academy of Sciences of the United States of America, 2009
- STIM1Mutation Associated with a Syndrome of Immunodeficiency and AutoimmunityThe New England Journal of Medicine, 2009
- A PACS-1, GGA3 and CK2 complex regulates CI-MPR traffickingThe EMBO Journal, 2006
- A mutation in Orai1 causes immune deficiency by abrogating CRAC channel functionNature, 2006