The IκB kinase complex is a regulator of mRNA stability. (22nd November 2018)

• Record Type: Journal Article
• Authors: Mikuda, Nadine; Kolesnichenko, Marina; Beaudette, Patrick; Popp, Oliver; Uyar, Bora; Sun, Wei; Tufan, Ahmet Bugra; Perder, Björn; Akalin, Altuna; Chen, Wei; Mertins, Philipp; Dittmar, Gunnar; Hinz, Michael; Scheidereit, Claus
• Is Part Of: EMBO journal. Volume 37:Number 24(2018)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2018-11-22
• Subjects: EDC4 -- IKK -- P bodies -- post‐transcriptional regulation -- RNA stability; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.201798658
• Languages: English
• ISSNs: 0261-4189

Abstract

Abstract: The IκB kinase (IKK) is considered to control gene expression primarily through activation of the transcription factor NF‐κB. However, we show here that IKK additionally regulates gene expression on post‐transcriptional level. IKK interacted with several mRNA‐binding proteins, including a Processing (P) body scaffold protein, termed enhancer of decapping 4 (EDC4). IKK bound to and phosphorylated EDC4 in a stimulus‐sensitive manner, leading to co‐recruitment of P body components, mRNA decapping proteins 1a and 2 (DCP1a and DCP2) and to an increase in P body numbers. Using RNA sequencing, we identified scores of transcripts whose stability was regulated via the IKK‐EDC4 axis. Strikingly, in the absence of stimulus, IKK‐EDC4 promoted destabilization of pro‐inflammatory cytokines and regulators of apoptosis. Our findings expand the reach of IKK beyond its canonical role as a regulator of transcription. Synopsis: The IκB kinase – best known to control transcription via NF‐κB activation – can bind mRNA decay factors and affect the formation of P bodies, revealing a new post‐transcriptional axis in inflammatory signalling. DNA damage, TNFα or IL‐1β stimulate an interaction between the IKK complex and mRNA decapping activator EDC4. IKK phosphorylates EDC4 to drive recruitment of decapping factors and an increase in P body numbers. The IKK‐EDC4 axis regulates stability of hundreds of mRNAs, including NF‐κB‐dependent and ‐independent transcripts. In the absence of external stimuli, IKK‐EDC4 promotes degradation of mRNAs encoding of pro‐inflammatory cytokines and regulators of apoptosis. Abstract : The IκB kinase binds mRNA decay factors and affects the formation of P bodies, extending its function beyond the canonical role as a regulator of NF‐kB‐dependent transcription.