Tristetraprolin‐driven regulatory circuit controls quality and timing of mRNA decay in inflammation

Abstract

Inflammatory gene activation must be rigorously controlled to ensure a rapid, but transient, response. In this work, a regulatory circuit is revealed that governs the destabilization of inflammatory mRNAs and plays an essential role in re-establishing immune homeostasis after inflammatory stimulus.

Translation control of TAK1 mRNA by hnRNP K modulates LPS-induced macrophage activation

“…In monocytes, a dependence of LPS-induced AKT activation on class I A of the three PIK3 classes (Cantley 2002) has been shown by RNAi-mediated PIK3CA silencing (Lee et al 2007). In contrast, RIP-Chip experiments with untreated macrophages and after LPS-activation employing an antibody against TTP revealed that TTP modulates the inflammatory response by controlling the stability of mRNAs, which encode pro-and antiinflammatory cytokines (Stoecklin et al 2008;Kratochvill et al 2011).…”

The RNA-binding protein tristetraprolin schedules apoptosis of pathogen-engaged neutrophils during bacterial infection

“…Tissuespecific deletion of Ttp using Ttp fl/fl LysM-Cre animals (referred to herein as TTP ΔM mice) demonstrated an essential function for myeloid TTP expression in the protection against LPS-induced toxic shock (12,16), but the role of TTP in immune responses to live pathogens has not been elucidated. To this end, we used a mouse model of invasive soft tissue infection with S. pyogenes.…”

“…The inflammatory symptoms are reduced upon blockage of TNF or IL-23 (14,15), but it remains possible that these cytokines act together or downstream of other defects resulting from TTP deficiency. Mice with LysM-Cre-driven Ttp deletion in macrophages and neutrophils are healthy despite an increased susceptibility to endotoxin-mediated septic shock (12,16). The role of TTP during bacterial infection and its specific function in neutrophils remain unknown.…”

“…Tristetraprolin (TTP, encoded by Ttp, also known as Zfp36) is an RNA-binding and -destabilizing protein that targets preferentially AU-rich elements (AREs) in 3′-UTRs for degradation by recruiting the CCR4-NOT deadenylase and the decapping complex (8). A multifaceted and still incompletely understood regulation of TTP by transcriptional, posttranscriptional, and posttranslational mechanisms orchestrates TTP activity, such that an efficient degradation occurs in the resolution phase of inflammation, and a premature degradation of target mRNAs is avoided (8)(9)(10)(11)(12)(13). Ttp-knockout mice are born healthy but suffer from granulocytic hyperplasia and develop a progressive and eventually lethal pleiotropic inflammation (14).…”

p38MAPK/MK2-mediated phosphorylation of RBM7 regulates the human nuclear exosome targeting complex

“…Shift assays with AU-rich and Random-RNAs (Kratochvill et al 2011) were performed basically as described in Tiedje et al (2012). To improve the shifts using 10 µg of HEK293T lysates overexpressing the indicated proteins, 20 µg of yeast tRNA in combination with 10 µg of salmon sperm DNA were preincubated with the lysates for 30 min prior to the addition of the DY681 and DY781-5 ′ labeled RNAs.…”