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A Chemical Genetic Screen Identifies ABHD12 as an Oxidized Phosphatidylserine Lipase

Reactive oxygen species (ROS) are transient, highly reactive intermediates or byproducts produced during oxygen metabolism. However, when innate mechanisms are unable to cope with sequestration of surplus ROS, it causes oxidative stress, where excess ROS damage biomolecules. Oxidized phosphatidylser...

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Autores principales: Kelkar, Dhanashree S., Ravikumar, Govindan, Mehendale, Neelay, Singh, Shubham, Joshi, Alaumy, Sharma, Ajay Kumar, Mhetre, Amol, Rajendran, Abinaya, Chakrapani, Harinath, Kamat, Siddhesh S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6420073/
https://www.ncbi.nlm.nih.gov/pubmed/30643283
http://dx.doi.org/10.1038/s41589-018-0195-0
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author Kelkar, Dhanashree S.
Ravikumar, Govindan
Mehendale, Neelay
Singh, Shubham
Joshi, Alaumy
Sharma, Ajay Kumar
Mhetre, Amol
Rajendran, Abinaya
Chakrapani, Harinath
Kamat, Siddhesh S.
author_facet Kelkar, Dhanashree S.
Ravikumar, Govindan
Mehendale, Neelay
Singh, Shubham
Joshi, Alaumy
Sharma, Ajay Kumar
Mhetre, Amol
Rajendran, Abinaya
Chakrapani, Harinath
Kamat, Siddhesh S.
author_sort Kelkar, Dhanashree S.
collection PubMed
description Reactive oxygen species (ROS) are transient, highly reactive intermediates or byproducts produced during oxygen metabolism. However, when innate mechanisms are unable to cope with sequestration of surplus ROS, it causes oxidative stress, where excess ROS damage biomolecules. Oxidized phosphatidylserine (PS), a pro-apoptotic “eat me” signal, is produced in response to elevated ROS, yet, little is known of its chemical composition and metabolism. Here, we report a small molecule that generates ROS in different mammalian cells, using which we detect, characterize and study oxidized PS in mammalian cells. We describe a chemical genetic screen to identify enzymes that regulate oxidized PS in mammalian cells, and find that the lipase ABHD12 hydrolyzes oxidized PS. We validate these findings in different physiological settings including primary peritoneal macrophages, and brains from Abhd12(–/–) knockout mice under inflammatory stress, and in the process functionally annotate an enzyme capable of regulating oxidized PS in vivo.
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spelling pubmed-64200732019-07-14 A Chemical Genetic Screen Identifies ABHD12 as an Oxidized Phosphatidylserine Lipase Kelkar, Dhanashree S. Ravikumar, Govindan Mehendale, Neelay Singh, Shubham Joshi, Alaumy Sharma, Ajay Kumar Mhetre, Amol Rajendran, Abinaya Chakrapani, Harinath Kamat, Siddhesh S. Nat Chem Biol Article Reactive oxygen species (ROS) are transient, highly reactive intermediates or byproducts produced during oxygen metabolism. However, when innate mechanisms are unable to cope with sequestration of surplus ROS, it causes oxidative stress, where excess ROS damage biomolecules. Oxidized phosphatidylserine (PS), a pro-apoptotic “eat me” signal, is produced in response to elevated ROS, yet, little is known of its chemical composition and metabolism. Here, we report a small molecule that generates ROS in different mammalian cells, using which we detect, characterize and study oxidized PS in mammalian cells. We describe a chemical genetic screen to identify enzymes that regulate oxidized PS in mammalian cells, and find that the lipase ABHD12 hydrolyzes oxidized PS. We validate these findings in different physiological settings including primary peritoneal macrophages, and brains from Abhd12(–/–) knockout mice under inflammatory stress, and in the process functionally annotate an enzyme capable of regulating oxidized PS in vivo. 2019-01-14 2019-02 /pmc/articles/PMC6420073/ /pubmed/30643283 http://dx.doi.org/10.1038/s41589-018-0195-0 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Kelkar, Dhanashree S.
Ravikumar, Govindan
Mehendale, Neelay
Singh, Shubham
Joshi, Alaumy
Sharma, Ajay Kumar
Mhetre, Amol
Rajendran, Abinaya
Chakrapani, Harinath
Kamat, Siddhesh S.
A Chemical Genetic Screen Identifies ABHD12 as an Oxidized Phosphatidylserine Lipase
title A Chemical Genetic Screen Identifies ABHD12 as an Oxidized Phosphatidylserine Lipase
title_full A Chemical Genetic Screen Identifies ABHD12 as an Oxidized Phosphatidylserine Lipase
title_fullStr A Chemical Genetic Screen Identifies ABHD12 as an Oxidized Phosphatidylserine Lipase
title_full_unstemmed A Chemical Genetic Screen Identifies ABHD12 as an Oxidized Phosphatidylserine Lipase
title_short A Chemical Genetic Screen Identifies ABHD12 as an Oxidized Phosphatidylserine Lipase
title_sort chemical genetic screen identifies abhd12 as an oxidized phosphatidylserine lipase
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6420073/
https://www.ncbi.nlm.nih.gov/pubmed/30643283
http://dx.doi.org/10.1038/s41589-018-0195-0
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