Dominant suppression of inflammation via targeted mutation of the mRNA destabilizing protein tristetraprolin


In myeloid cells, the mRNA-destabilizing protein tristetraprolin (TTP) is induced and extensively phosphorylated in response to LPS. To investigate the role of two specific phosphorylations, at serines 52 and 178, we created a mouse strain in which those residues were replaced by nonphosphorylatable alanine residues. The mutant form of TTP was constitutively degraded by the proteasome and therefore expressed at low levels, yet it functioned as a potent mRNA destabilizing factor and inhibitor of the expression of many inflammatory mediators. Mice expressing only the mutant form of TTP were healthy and fertile, and their systemic inflammatory responses to LPS were strongly attenuated. Adaptive immune responses and protection against infection by Salmonella typhimurium were spared. A single allele encoding the mutant form of TTP was sufficient for enhanced mRNA degradation and underexpression of inflammatory mediators. Therefore, the equilibrium between unphosphorylated and phosphorylated TTP is a critical determinant of the inflammatory response, and manipulation of this equilibrium may be a means of treating inflammatory pathologies.

Publication DOI:
Divisions: College of Health & Life Sciences
College of Health & Life Sciences > School of Biosciences
Additional Information: Copyright © 2015 The Authors This is an open-access article distributed under the terms of the CC-BY 3.0 Unported license.
Uncontrolled Keywords: Immunology and Allergy,Immunology
Publication ISSN: 1550-6606
Last Modified: 26 Apr 2024 07:15
Date Deposited: 30 Aug 2019 10:32
Full Text Link:
Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
https://www.jim ... ab-article-info (Publisher URL)
PURE Output Type: Article
Published Date: 2015-06-19
Accepted Date: 2015-04-27
Authors: Ross, Ewan A. (ORCID Profile 0000-0001-5733-9361)
Smallie, Tim
Ding, Qize
O'Neil, John D.
Cunliffe, Helen E.
Tang, Tina
Rosner, Dalya R.
Klevernic, Iva
Morrice, Nicholas A.
Monaco, Claudia
Cunningham, Adam F.
Buckley, Christopher D.
Saklatvala, Jeremy
Dean, Jonathan L.
Clark, Andrew R.



Version: Published Version

License: Creative Commons Attribution

| Preview

Export / Share Citation


Additional statistics for this record