2. Academic Validation
  3. Immunomodulatory lysophosphatidylserines are regulated by ABHD16A and ABHD12 interplay

Immunomodulatory lysophosphatidylserines are regulated by ABHD16A and ABHD12 interplay

  • Nat Chem Biol. 2015 Feb;11(2):164-71. doi: 10.1038/nchembio.1721.
Siddhesh S Kamat 1,  Kaddy Camara 2,  William H Parsons 1,  Dong-Hui Chen 3,  Melissa M Dix 1,  Thomas D Bird 4,  Amy R Howell 2,  Benjamin F Cravatt 1
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Chemistry, University of Connecticut, Storrs, Connecticut.
  • 3 Department of Neurology, University of Washington, Seattle, Washington.
  • 4 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.
PMID: 25580854 DOI: 10.1038/nchembio.1721
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.

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