Immunomodulatory lysophosphatidylserines are regulated by ABHD16A and ABHD12 interplay

• Published in: Nature chemical biology Vol. 11; no. 2; pp. 164 - 171
• Main Authors: Kamat, Siddhesh S, Camara, Kaddy, Parsons, William H, Chen, Dong-Hui, Dix, Melissa M, Bird, Thomas D, Howell, Amy R, Cravatt, Benjamin F
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.02.2015; Nature Publishing Group
• Subjects: 631/250; 631/45; 631/92/287; 631/92/607; 82; 82/58; Animals; Biochemical Engineering; Biochemistry; Bioorganic Chemistry; Brain; Brain - enzymology; Brain - immunology; Brain - metabolism; Cell Biology; Cell Line; Chemistry; Chemistry/Food Science; Cytokines - immunology; Cytokines - metabolism; Hearing loss; Humans; Immunologic Factors - immunology; Immunologic Factors - metabolism; Immunology; Lipids; Lysophospholipids - immunology; Lysophospholipids - metabolism; Macrophages - enzymology; Macrophages - immunology; Macrophages - metabolism; Male; Mammals; Metabolism; Mice, Knockout; Monoacylglycerol Lipases - genetics; Mutation; Phospholipases - antagonists & inhibitors; Phospholipases - genetics; Signaling
• ISSN: 1552-4450; 1552-4469; 1552-4469
• DOI: 10.1038/nchembio.1721

ABHD16A is identified as a major enzyme catalyzing production of lyso-PS from phosphatidylserine (PS). A new ABHD16A inhibitor and knockout mice show a dynamic interplay occurring during inflammation between ABHD16A and disease-linked ABHD12, an enzyme that degrades lyso-PS. ABHD16A is identified as a major enzyme catalyzing production of lyso-PS from phosphatidylserine (PS). A new ABHD16A inhibitor and knockout mice show a dynamic interplay occurring during inflammation between ABHD16A and disease-linked ABHD12, an enzyme that degrades lyso-PS. 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.