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Immunomodulatory lysophosphatidylserines are regulated by ABHD16A and ABHD12 interplay

Academic Article
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Overview

authors

  • Kamat, S. S.
  • Camara, K.
  • Parsons, W. H.
  • Chen, D. H.
  • Dix, Melissa
  • Bird, T. D.
  • Howell, A. R.
  • Cravatt, Benjamin

publication date

  • 2015

journal

  • Nature Chemical Biology  Journal

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.

subject areas

  • Animals
  • Brain
  • Cell Line
  • Cytokines
  • Humans
  • Immunologic Factors
  • Lysophospholipids
  • Macrophages
  • Male
  • Mice, Knockout
  • Monoacylglycerol Lipases
  • Mutation
  • Phospholipases
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Identity

PubMed Central ID

  • PMC4301979

International Standard Serial Number (ISSN)

  • 1552-4450

Digital Object Identifier (DOI)

  • 10.1038/nchembio.1721

PubMed ID

  • 25580854
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Additional Document Info

start page

  • 164

end page

  • 171

volume

  • 11

issue

  • 2

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