title: Immunomodulatory lysophosphatidylserines are regulated by ABHD16A and ABHD12 interplay.
abstract: Lysophosphatidylserines (lyso-PSs) are a class of signaling lipids that regulate immunological and neurological processes. The metabolism of lyso-PSs remains poorly understood in vivo. Recently, we determined that ABHD12 is a major brain lyso-PS lipase, implicating lyso-PSs in the neurological disease polyneuropathy, hearing loss, ataxia, retinitis pigmentosa and cataract (PHARC), which is caused by null mutations in the ABHD12 gene. Here, we couple activity-based profiling with pharmacological and genetic methods to annotate the poorly characterized enzyme ABHD16A as a phosphatidylserine (PS) lipase that generates lyso-PS in mammalian systems. We describe a small-molecule inhibitor of ABHD16A that depletes lyso-PSs from cells, including lymphoblasts derived from subjects with PHARC. In mouse macrophages, disruption of ABHD12 and ABHD16A respectively increases and decreases both lyso-PSs and lipopolysaccharide-induced cytokine production. Finally, Abhd16a(-/-) mice have decreased brain lyso-PSs, which runs counter to the elevation in lyso-PS in Abhd12(-/-) mice. Our findings illuminate an ABHD16A-ABHD12 axis that dynamically regulates lyso-PS metabolism in vivo, designating these enzymes as potential targets for treating neuroimmunological disorders.
authors.affiliation: 1] Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California. [2] The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California.
authors.forename: Siddhesh S
authors.initials: SS
authors.lastname: Kamat
authors.affiliation: Department of Chemistry, University of Connecticut, Storrs, Connecticut.
authors.forename: Kaddy
authors.identifier: 0000000226188385
authors.initials: K
authors.lastname: Camara
authors.affiliation: 1] Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California. [2] The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California.
authors.forename: William H
authors.initials: WH
authors.lastname: Parsons
authors.affiliation: Department of Neurology, University of Washington, Seattle, Washington.
authors.forename: Dong-Hui
authors.initials: DH
authors.lastname: Chen
authors.affiliation: 1] Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California. [2] The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California.
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Dix
authors.affiliation: 1] Department of Neurology, University of Washington, Seattle, Washington. [2] Department of Medicine, University of Washington, Seattle, Washington. [3] VA Puget Sound Health Care System, Seattle, Washington.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Bird
authors.affiliation: Department of Chemistry, University of Connecticut, Storrs, Connecticut.
authors.forename: Amy R
authors.initials: AR
authors.lastname: Howell
authors.affiliation: 1] Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California. [2] The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California.
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
mesh_terms: D000818:Animals; D001921:Brain / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007155:Immunologic Factors / Q000276:immunology / Q000378:metabolism*; D008246:Lysophospholipids / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D008297:Male; D018345:Mice, Knockout; D008994:Monoacylglycerol Lipases / Q000235:genetics*; D009154:Mutation; D010740:Phospholipases / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: D016207:Cytokines; D007155:Immunologic Factors; D008246:Lysophospholipids; C025059:lysophosphatidylserine; D010740:Phospholipases; C000597009:ABHD16A protein, mouse; C527260:Abhd12 protein, mouse; D008994:Monoacylglycerol Lipases