☆ 4.6 Article

Cool-temperature-mediated activation of phospholipase C-γ2 in the human hereditary disease PLAID

CELLULAR SIGNALLING (2016)

Journal

CELLULAR SIGNALLING

Volume 28, Issue 9, Pages 1237-1251

Publisher

ELSEVIER SCIENCE INC

DOI: 10.1016/j.cellsig.2016.05.010

Keywords

Phospholipase C-gamma(2); lnositol phospholipid; Rac2 GTPase; Split PH domain; Autoinhibition; Cold temperature sensitivity

Funding

Deutsche Forschungsgemeinschaft (DFG) [SFB 1074, TP A8]
SFB [1074]
DFG Research Training Group [GRK1041]
International Graduate School in Molecular Medicine Ulm (IGradU) within the Excellence Initiative of the German Federal and State Governments [GSC 279]

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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 trans location. 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 PLCy 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. (C) 2016 Elsevier Inc. All rights reserved.

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