Genetic variant in 3' untranslated region of the mouse pycard gene regulates inflammasome activity.

Autor:	Ritchey B; Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, United States., Hai Q; Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, United States., Han J; Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, United States., Barnard J; Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, United States., Smith JD; Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, United States.; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, United States.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2021 Jul 01; Vol. 10. Date of Electronic Publication: 2021 Jul 01.
DOI:	10.7554/eLife.68203
Abstrakt:	Quantitative trait locus mapping for interleukin-1β release after inflammasome priming and activation was performed on bone-marrow-derived macrophages (BMDM) from an AKRxDBA/2 mouse strain intercross. The strongest associated locus mapped very close to the Pycard gene on chromosome 7, which codes for the inflammasome adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC). The DBA/2 and AKR Pycard genes only differ at a single-nucleotide polymorphism (SNP) in their 3' untranslated region (UTR). DBA/2 vs. AKR BMDM had increased levels of Pycard mRNA expression and ASC protein, and increased inflammasome speck formation, which was associated with increased Pycard mRNA stability without an increased transcription rate. CRISPR/Cas9 gene editing was performed on DBA/2 embryonic stem cells to change the Pycard 3'UTR SNP from the DBA/2 to the AKR allele. This single base change significantly reduced Pycard expression and inflammasome activity after cells were differentiated into macrophages due to reduced Pycard mRNA stability. Competing Interests: BR, QH, JH, JB, JS No competing interests declared (© 2021, Ritchey et al.)
Databáze:	MEDLINE
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