The IκB kinase complex is a regulator of mRNA stability

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.

More than just an IκB kinase: the IKK complex coordinates mRNA stability and transcription

“…Removal of the 5′ mRNA cap by DCP1a and DCP2 then allows 5′–3′ mRNA degradation by the exonuclease XRN1 (Chang et al , ). Mikuda et al () established that both IKKγ and IKKβ inducibly interact with EDC4 in response not only to IR treatment but also to TNFα, establishing the relevance of this complex to inflammatory signalling. Importantly, EDC4 is a substrate of IKKβ and mutation of these IKK phosphorylation sites abolished both its interaction with DCP1a and DCP2 as well as the stimulus‐induced increase in P‐body numbers, the sites of mRNA degradation and storage within the cytoplasm.…”

“…Adding to the growing evidence for the IKK complex being a pleiotropic regulator of inflammatory and stress responses is the report from Mikuda et al (). This article defines a new role for the IKK complex as a regulator of mRNA stability.…”

“…Mikuda et al () used SILAC proteomics to identify novel IKKγ‐associated proteins following treatment with ionising radiation (IR), a known inducer of IKK activity and NF‐κB signalling (McCool & Miyamoto, ). Unexpectedly, the authors found that DNA damage induced the association of IKKγ with a number of RNA binding proteins (RBPs).…”

“…IκB kinase and EDC4 together regulate a large number of target mRNAs. Mikuda et al () demonstrated that these include both NF‐κB‐dependent and NF‐κB‐independent transcripts. Interestingly, the IKK/EDC4 complex differentially regulates mRNA stability both before and after cell stress.…”

“…Alternatively, in the absence of stimulation IKKβ might fulfil a kinase‐independent scaffold function, as has been shown previously (Tsuchiya et al , ). Moreover, whether the decapping complex is actually responsible for the IKK‐dependent effects, either before or after cell stimulation, was not formally established by Mikuda et al (). Indeed, it is possible that phosphorylation of EDC4 by IKKβ may have other effects, possibly involving the other IKK‐associated RBPs (which did not include the other members of the decapping complex).…”