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A Knock-In Tristetraprolin (TTP) Zinc Finger Point Mutation in Mice: Comparison with Complete TTP Deficiency

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2018

Mol Cell Biol. 2018 Jan 29;38(4). pii: e00488-17. doi: 10.1128/MCB.00488-17. Print 2018 Feb 15.

A Knock-In Tristetraprolin (TTP) Zinc Finger Point Mutation in Mice: Comparison with Complete TTP Deficiency

WS Lai;DJ Stumpo;L Qiu;R Faccio;PJ Blackshear

Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA. Department of Orthopedics, Washington University School of Medicine, St. Louis, Missouri, USA. Departments of Medicine and Biochemistry, Duke University Medical Center, Durham, North Carolina, USA.

Service type: Knock-in mice

Abstract

Tristetraprolin (TTP) is a tandem CCCH zinc finger protein that can bind to AU-rich element-containing mRNAs and promote their decay. TTP knockout mice develop a severe inflammatory syndrome, largely due to excess tumor necrosis factor (TNF), whose mRNA is a direct target of TTP binding and destabilization. TTP's RNA binding activity and its ability to promote mRNA decay are lost when one of the zinc-coordinating residues of either zinc finger is mutated. To address several long-standing questions about TTP activity in intact animals, we developed a knock-in mouse with a cysteine-to-arginine mutation within the first zinc finger. Homozygous knock-in mice developed a severe inflammatory syndrome that was essentially identical to that of complete TTP deficiency, suggesting that TTP's critical anti-inflammatory role in mammalian physiology is secondary to its ability to bind RNA. In addition, there was no evidence for a "dominant-negative" effect of the mutant allele in heterozygotes, as suggested by previous experiments. Finally, mRNA decay experiments in mutant macrophages demonstrated that TTP can regulate the stability of its own mRNA, albeit to a minor extent. These studies suggest that RNA binding is an essential first step in the physiological activities of members of this protein family.

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