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A cellular genome-wide association study reveals human variation in microtubule stability and a role in inflammatory cell death

Pyroptosis is proinflammatory cell death that occurs in response to certain microbes. Activation of the protease caspase-1 by molecular platforms called inflammasomes is required for pyroptosis. We performed a cellular genome-wide association study (GWAS) using Salmonella typhimurium infection of hu...

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Autores principales: Salinas, Raul E., Ogohara, Cassandra, Thomas, Monica I., Shukla, Kajal P., Miller, Samuel I., Ko, Dennis C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3873895/
https://www.ncbi.nlm.nih.gov/pubmed/24173717
http://dx.doi.org/10.1091/mbc.E13-06-0294
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author Salinas, Raul E.
Ogohara, Cassandra
Thomas, Monica I.
Shukla, Kajal P.
Miller, Samuel I.
Ko, Dennis C.
author_facet Salinas, Raul E.
Ogohara, Cassandra
Thomas, Monica I.
Shukla, Kajal P.
Miller, Samuel I.
Ko, Dennis C.
author_sort Salinas, Raul E.
collection PubMed
description Pyroptosis is proinflammatory cell death that occurs in response to certain microbes. Activation of the protease caspase-1 by molecular platforms called inflammasomes is required for pyroptosis. We performed a cellular genome-wide association study (GWAS) using Salmonella typhimurium infection of human lymphoblastoid cell lines as a means of dissecting the genetic architecture of susceptibility to pyroptosis and identifying unknown regulatory mechanisms. Cellular GWAS revealed that a common human genetic difference that regulates pyroptosis also alters microtubule stability. An intergenic single-nucleotide polymorphism on chromosome 18 is associated with decreased pyroptosis and increased expression of TUBB6 (tubulin, β 6 class V). TUBB6 is unique among tubulin isoforms in that its overexpression can completely disrupt the microtubule network. Cells from individuals with higher levels of TUBB6 expression have lower microtubule stability and less pyroptosis. Reducing TUBB6 expression or stabilizing microtubules pharmacologically with paclitaxel (Taxol) increases pyroptosis without affecting the other major readout of caspase-1 activation, interleukin-1β secretion. The results reveal a new role for microtubules and possibly specific tubulin isoforms in the execution of pyroptosis. Furthermore, the finding that there is common diversity in TUBB6 expression and microtubule stability could have broad consequences for other microtubule-dependent phenotypes, diseases, and pharmacological responses.
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spelling pubmed-38738952014-03-16 A cellular genome-wide association study reveals human variation in microtubule stability and a role in inflammatory cell death Salinas, Raul E. Ogohara, Cassandra Thomas, Monica I. Shukla, Kajal P. Miller, Samuel I. Ko, Dennis C. Mol Biol Cell Articles Pyroptosis is proinflammatory cell death that occurs in response to certain microbes. Activation of the protease caspase-1 by molecular platforms called inflammasomes is required for pyroptosis. We performed a cellular genome-wide association study (GWAS) using Salmonella typhimurium infection of human lymphoblastoid cell lines as a means of dissecting the genetic architecture of susceptibility to pyroptosis and identifying unknown regulatory mechanisms. Cellular GWAS revealed that a common human genetic difference that regulates pyroptosis also alters microtubule stability. An intergenic single-nucleotide polymorphism on chromosome 18 is associated with decreased pyroptosis and increased expression of TUBB6 (tubulin, β 6 class V). TUBB6 is unique among tubulin isoforms in that its overexpression can completely disrupt the microtubule network. Cells from individuals with higher levels of TUBB6 expression have lower microtubule stability and less pyroptosis. Reducing TUBB6 expression or stabilizing microtubules pharmacologically with paclitaxel (Taxol) increases pyroptosis without affecting the other major readout of caspase-1 activation, interleukin-1β secretion. The results reveal a new role for microtubules and possibly specific tubulin isoforms in the execution of pyroptosis. Furthermore, the finding that there is common diversity in TUBB6 expression and microtubule stability could have broad consequences for other microtubule-dependent phenotypes, diseases, and pharmacological responses. The American Society for Cell Biology 2014-01-01 /pmc/articles/PMC3873895/ /pubmed/24173717 http://dx.doi.org/10.1091/mbc.E13-06-0294 Text en © 2014 Salinas et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society of Cell Biology.
spellingShingle Articles
Salinas, Raul E.
Ogohara, Cassandra
Thomas, Monica I.
Shukla, Kajal P.
Miller, Samuel I.
Ko, Dennis C.
A cellular genome-wide association study reveals human variation in microtubule stability and a role in inflammatory cell death
title A cellular genome-wide association study reveals human variation in microtubule stability and a role in inflammatory cell death
title_full A cellular genome-wide association study reveals human variation in microtubule stability and a role in inflammatory cell death
title_fullStr A cellular genome-wide association study reveals human variation in microtubule stability and a role in inflammatory cell death
title_full_unstemmed A cellular genome-wide association study reveals human variation in microtubule stability and a role in inflammatory cell death
title_short A cellular genome-wide association study reveals human variation in microtubule stability and a role in inflammatory cell death
title_sort cellular genome-wide association study reveals human variation in microtubule stability and a role in inflammatory cell death
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3873895/
https://www.ncbi.nlm.nih.gov/pubmed/24173717
http://dx.doi.org/10.1091/mbc.E13-06-0294
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