title: A cellular genome-wide association study reveals human variation in microtubule stability and a role in inflammatory cell death.
abstract: 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.
authors.affiliation: Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC 27710 Department of Medicine and Center for Human Genome Variation, School of Medicine, Duke University, Durham, NC 27710 Department of Microbiology, University of Washington, Seattle, WA 98195 Departments of Medicine, Genome Sciences, and Immunology, University of Washington, Seattle, WA 98195.
authors.forename: Raul E
authors.initials: RE
authors.lastname: Salinas
authors.forename: Cassandra
authors.initials: C
authors.lastname: Ogohara
authors.forename: Monica I
authors.initials: MI
authors.lastname: Thomas
authors.forename: Kajal P
authors.initials: KP
authors.lastname: Shukla
authors.forename: Samuel I
authors.initials: SI
authors.lastname: Miller
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Ko
mesh_terms: D017209:Apoptosis; D002454:Cell Differentiation; D015870:Gene Expression; D015894:Genome, Human; D055106:Genome-Wide Association Study; D057809:HEK293 Cells; D006801:Humans; D008870:Microtubules / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology; D020641:Polymorphism, Single Nucleotide; D055550:Protein Stability; D014404:Tubulin / Q000502:physiology*; D050257:Tubulin Modulators / Q000494:pharmacology
chemical_list: C000590680:TUBB6 protein, human; D014404:Tubulin; D050257:Tubulin Modulators; D017239:Paclitaxel