title: Cool-temperature-mediated activation of phospholipase C-γ2 in the human hereditary disease PLAID.
abstract: Deletions in the gene encoding signal-transducing inositol phospholipid-specific phospholipase C-γ2 (PLCγ2) are associated with the novel human hereditary disease PLAID (PLCγ2-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, PLCγ2, is currently lacking. PLCγ2 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. PLCγ2 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 PLCγ2 is primarily due to loss of SH-region-mediated autoinhibition and/or enhanced plasma membrane translocation. Here, we show that the two PLAID PLCγ2 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 PLCγ2 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 PLCγ 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.
authors.affiliation: Institute of Pharmacology and Toxicology, Ulm University Medical Center, 89070 Ulm, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Schade
authors.affiliation: Institute of Pharmacology and Toxicology, Ulm University Medical Center, 89070 Ulm, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Walliser
authors.affiliation: Institute of Pharmacology and Toxicology, Ulm University Medical Center, 89070 Ulm, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Wist
authors.affiliation: Institute of Pharmacology and Toxicology, Ulm University Medical Center, 89070 Ulm, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Haas
authors.affiliation: Institute of Pharmacology and Toxicology, Ulm University Medical Center, 89070 Ulm, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Vatter
authors.affiliation: Institute of Medical Systems Biology, Ulm University, 89081 Ulm, Germany.
authors.forename: Johann M
authors.initials: JM
authors.lastname: Kraus
authors.affiliation: Environmental Ergonomics Research Centre, Loughborough University, Leicestershire LE11 3TU, United Kingdom.
authors.forename: Davide
authors.initials: D
authors.lastname: Filingeri
authors.affiliation: Environmental Ergonomics Research Centre, Loughborough University, Leicestershire LE11 3TU, United Kingdom.
authors.forename: George
authors.initials: G
authors.lastname: Havenith
authors.affiliation: Institute of Medical Systems Biology, Ulm University, 89081 Ulm, Germany.
authors.forename: Hans A
authors.initials: HA
authors.lastname: Kestler
authors.affiliation: Allergic Inflammation Unit, Laboratory of Allergic Diseases, NIAID, NIH, Bethesda, MD 20892, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Milner
authors.affiliation: Institute of Pharmacology and Toxicology, Ulm University Medical Center, 89070 Ulm, Germany. Electronic address: peter.gierschik@uni-ulm.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Gierschik
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D003080:Cold Temperature; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000378:metabolism; D005091:Exons / Q000235:genetics; D017353:Gene Deletion; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000201:enzymology* / Q000473:pathology; D007527:Isoenzymes / Q000378:metabolism; D051966:Phospholipase C gamma / Q000378:metabolism*; D014176:Protein Biosynthesis; D000072417:Protein Domains
chemical_list: D007527:Isoenzymes; D066246:ErbB Receptors; D051966:Phospholipase C gamma
keywords: Autoinhibition; Cold temperature sensitivity; Inositol phospholipid; Phospholipase C-γ(2); Rac2 GTPase; Split PH domain