6
Interleukin 1alpha-induced NFkappaB activation and chemokine mRNA stabilization diverge at IRAK1.
J Biol Chem. 2008 Jun 6; 283(23):15689-93
Joseph Mizgerd, Boston University School of Medicine, MA, USA. F1000 Respiratory Disorders
20 Jun 2008 | New Finding
This paper is useful for guiding research on the mechanisms of how inflammatory signalling increases cytokine transcript stability.
Cytokine expression during inflammation is mediated by a combination of increased transcription (e.g. by NF-kappaB transcription factors) and decreased transcript degradation (via less well-defined pathways). After IL-1alpha stimulation of the IL-1R1 receptor, both IL-1 receptor-associated kinase 1 (IRAK1) and TNF-associated receptor 6 (TRAF6), recruited to the receptor-signalling complex by IRAK1, were shown to be essential for NF-kappaB activation. In contrast, IRAK1, but not TRAF6, was essential for IL-1alpha-induced stabilization of transcripts for the neutrophil chemoattractant KC (CXCL1). In contrast to mRNA stability, the phosphorylation of p38 did require TRAF6 in this setting, suggesting this transcript stabilization to be independent of p38. Overexpression studies complemented the loss-of-function results by showing that IRAK1, but not TRAF6, was sufficient to increase transcript stability and that a mutant IRAK1 which could not bind TRAF6 was also sufficient to increase transcript stability.
Thus, IRAK1 enhances transcript stability via a TRAF6-independent signalling pathway which does not appear to require p38. Elucidation of this novel pathway will likely provide insights into acute and chronic inflammatory diseases and targets for therapeutic intervention.
Competing interests: No potential interests relevant to this article were reported.
Mizgerd J: "This paper is useful for guiding research on the mechanisms of how inflammatory signalling increases..." Evaluation of: [Hartupee J et al. Interleukin 1alpha-induced NFkappaB activation and chemokine mRNA stabilization diverge at IRAK1. J Biol Chem. 2008 Jun 6; 283(23):15689-93; doi: 10.1074/jbc.M801346200]. Faculty of 1000, 20 Jun 2008. F1000.com/1115077#eval571053
Short form
Mizgerd J: 2008. F1000.com/1115077#eval571053
Faculty of 1000 evaluations, dissents and comments for [Hartupee J et al. Interleukin 1alpha-induced NFkappaB activation and chemokine mRNA stabilization diverge at IRAK1. J Biol Chem. 2008 Jun 6; 283(23):15689-93; doi: 10.1074/jbc.M801346200]. Faculty of 1000, 20 Jun 2008. F1000.com/1115077
Short form
Faculty of 1000: 2008. F1000.com/1115077
Interleukin 1alpha (IL-1alpha) is capable of driving pro-inflammatory gene expression through both the initiation of transcription and by prolonging the half-life of short-lived mRNAs. Although the signaling events linking the IL-1 receptor to the activation of NFkappaB and the initiation of transcription have been well characterized, less is known about the signaling events linking to mRNA stabilization. As a model to study the control of mRNA stability we have used the mouse chemokine KC, expression of which requires both NFkappaB-driven transcription and stabilization of the constitutively unstable mRNA. We have evaluated the role of signaling adaptors known to play a role in IL-1alpha-driven NFkappaB activation in the generation of mRNA stability. Surprisingly, although TRAF6 is essential for NFkappaB activation, it is not required for IL-1alpha-induced mRNA stabilization. IRAK1, which is recognized to function upstream of TRAF6, is required for both mRNA stabilization and activation of NFkappaB. Consistent with the previous findings, the TRAF6 interaction sites in IRAK1 are required for NFkappaB activation but do not play a role in mRNA stabilization. These findings indicate that signals from the IL-1 receptor segregate into at least two separate pathways at the level of IRAK1; one couples through TRAF6 to NFkappaB activation while a second utilizes a TRAF6-independent pathway that is responsible for mRNA stabilization.
DOI: 10.1074/jbc.M801346200
PMID: 18411265
Sign in/get access to leave a comment.
No comments yet.