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Title: Cool-temperature-mediated activation of phospholipase C-[gamma]2 in the human hereditary disease PLAID
Authors: Schade, Anja
Walliser, Claudia
Wist, Martin
Haas, Jennifer
Vatter, Petra
Kraus, Johann M.
Filingeri, Davide
Havenith, George
Kestler, Hans A.
Milner, Joshua D.
Gierschik, Peter
Keywords: Phospholipase C-[gamma]2
Inositol phospholipid
Rac2 GTPase
Split pH domain
Cold temperature sensitivity
Issue Date: 2016
Publisher: © Elsevier
Citation: SCHADE, A. ... et al., 2016. Cool-temperature-mediated activation of phospholipase C-[gamma]2 in the human hereditary disease PLAID. Cellular Signalling, 28 (9), pp. 1237–1251.
Abstract: Deletions in the gene encoding signal-transducing inositol phospholipid-specific phospholipase C-[gamma]2 (PLC[gamma]2) are associated with the novel human hereditary disease PLAID (PLC[gamma]2-associated antibody deficiency and immune dysregulation). PLAID is characterized by a rather puzzling concurrence of augmented and diminished functions of the immune system, such as cold urticaria triggered by only minimal decreases in temperature, autoimmunity, and immunodeficiency. Understanding of the functional effects of the genomic alterations at the level of the affected enzyme, PLC[gamma]2, is currently lacking. PLC[gamma]2 is critically involved in coupling various cell surface receptors to regulation of important functions of immune cells such as mast cells, B cells, monocytes/macrophages, and neutrophils. PLC[gamma]2 is unique by carrying three Src (SH) and one split pleckstrin homology domain (spPH) between the two catalytic subdomains (spPHn-SH2n-SH2c-SH3-spPHc). Prevailing evidence suggests that activation of PLC[gamma]2 is primarily due to loss of SH-region-mediated autoinhibition and/or enhanced plasma membrane translocation. Here, we show that the two PLAID PLC[gamma]2 mutants lacking portions of the SH region are strongly (> 100-fold), rapidly, and reversibly activated by cooling by only a few degrees. We found that the mechanism(s) underlying PLC[gamma]2 PLAID mutant activation by cool temperatures is distinct from a mere loss of SH-region-mediated autoinhibition and dependent on both the integrity and the pliability of the spPH domain. The results suggest a new mechanism of PLC[gamma] activation with unique thermodynamic features and assign a novel regulatory role to its spPH domain. Involvement of this mechanism in other human disease states associated with cooling such as exertional asthma and certain acute coronary events appears an intriguing possibility.
Description: This paper was accepted for publication in the journal Cellular Signalling and the definitive published version is available at http://dx.doi.org/10.1016/j.cellsig.2016.05.010.
Version: Accepted for publication
DOI: 10.1016/j.cellsig.2016.05.010
URI: https://dspace.lboro.ac.uk/2134/21459
Publisher Link: http://dx.doi.org/10.1016/j.cellsig.2016.05.010
ISSN: 0898-6568
Appears in Collections:Published Articles (Design School)

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