Functional genetic screen of human diversity reveals that a methionine salvage enzyme regulates inflammatory cell death
| العنوان: | Functional genetic screen of human diversity reveals that a methionine salvage enzyme regulates inflammatory cell death |
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| المؤلفون: | Dale Whittington, Richard A. Pfuetzner, Cassandra Ogohara, Amy L. Stark, Eric R. Gamazon, Tarah D. Holden, Kajal P. Shukla, Dennis C. Ko, Joshua M. Akey, Mitchell J. Brittnacher, Mark M. Wurfel, Samuel I. Miller, Christine Fong, M. Eileen Dolan, Matthew C. Radey |
| المصدر: | Proceedings of the National Academy of Sciences. 109 |
| بيانات النشر: | Proceedings of the National Academy of Sciences, 2012. |
| سنة النشر: | 2012 |
| مصطلحات موضوعية: | Adult, Salmonella typhimurium, Programmed cell death, Quantitative Trait Loci, Apoptosis, Bone Marrow Cells, HapMap Project, Biology, Polymorphism, Single Nucleotide, Mice, Young Adult, chemistry.chemical_compound, Methionine, Commentaries, Animals, Humans, Genetic Predisposition to Disease, Allele, Aged, Aged, 80 and over, Genetics, Thionucleosides, Multidisciplinary, Deoxyadenosines, Caspase 1, HEK 293 cells, Pyroptosis, Genetic Variation, Middle Aged, Salvage enzyme, Caspase 9, Mice, Inbred C57BL, HEK293 Cells, PNAS Plus, chemistry, Salmonella Infections, Apoptosis Regulatory Proteins, Genetic screen |
| الوصف: | Genome-wide association studies can identify common differences that contribute to human phenotypic diversity and disease. When genome-wide association studies are combined with approaches that test how variants alter physiology, biological insights can emerge. Here, we used such an approach to reveal regulation of cell death by the methionine salvage pathway. A common SNP associated with reduced expression of a putative methionine salvage pathway dehydratase, apoptotic protease activating factor 1 (APAF1)-interacting protein ( APIP ), was associated with increased caspase-1–mediated cell death in response to Salmonella . The role of APIP in methionine salvage was confirmed by growth assays with methionine-deficient media and quantitation of the methionine salvage substrate, 5′-methylthioadenosine. Reducing expression of APIP or exogenous addition of 5′-methylthioadenosine increased Salmonellae-induced cell death. Consistent with APIP originally being identified as an inhibitor of caspase-9–dependent apoptosis, the same allele was also associated with increased sensitivity to the chemotherapeutic agent carboplatin. Our results show that common human variation affecting expression of a single gene can alter susceptibility to two distinct cell death programs. Furthermore, the same allele that promotes cell death is associated with improved survival of individuals with systemic inflammatory response syndrome, suggesting a possible evolutionary pressure that may explain the geographic pattern observed for the frequency of this SNP. Our study shows that in vitro association screens of disease-related traits can not only reveal human genetic differences that contribute to disease but also provide unexpected insights into cell biology. |
| تدمد: | 1091-6490 0027-8424 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::99a1652e1fbfc5a1ccfa29132ce4181aTest https://doi.org/10.1073/pnas.1206701109Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....99a1652e1fbfc5a1ccfa29132ce4181a |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10916490 00278424 |
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