The IκB kinase complex regulates the stability of cytokine-encoding mRNA induced by TLR-IL-1R by controlling degradation of regnase-1.
Toll-like receptor (TLR) signaling activates the inhibitor of transcription factor NF-κB (IκB) kinase (IKK) complex, which governs NF-κB-mediated transcription during inflammation. The RNase regnase-1 serves a critical role in preventing autoimmunity by controlling the stability of mRNAs that encode cytokines. Here we show that the IKK complex controlled the stability of mRNA for interleukin 6 (IL-6) by phosphorylating regnase-1 in response to stimulation via the IL-1 receptor (IL-1R) or TLR. Phosphorylated regnase-1 underwent ubiquitination and degradation. Regnase-1 was reexpressed in IL-1R- or TLR-activated cells after a period of lower expression. Regnase-1 mRNA was negatively regulated by regnase-1 itself via a stem-loop region present in the regnase-1 3' untranslated region. Our data demonstrate that the IKK complex phosphorylates not only IκBα, thereby activating transcription, but also regnase-1, thereby releasing a 'brake' on IL-6 mRNA expression.
Laboratory of Host Defense, World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan.
Hidenori
H
Iwasaki
Osamu
O
Takeuchi
Shunsuke
S
Teraguchi
Kazufumi
K
Matsushita
Takuya
T
Uehata
Kanako
K
Kuniyoshi
Takashi
T
Satoh
Tatsuya
T
Saitoh
Mutsuyoshi
M
Matsushita
Daron M
DM
Standley
Shizuo
S
Akira
D000818:Animals; D006801:Humans; D051379:Mice; D020816:Amino Acid Motifs; D045744:Cell Line, Tumor; D016207:Cytokines / Q000235:genetics; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006367:HeLa Cells; D051550:I-kappa B Kinase / Q000378:metabolism; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics; D018345:Mice, Knockout; D008954:Models, Biological; D011485:Protein Binding; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D012260:Ribonucleases / Q000378:metabolism; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism; D014157:Transcription Factors
D016207:Cytokines; D051550:I-kappa B Kinase; D053592:Interleukin-1 Receptor-Associated Kinases; D015850:Interleukin-6; D017472:Receptors, Interleukin-1; D012260:Ribonucleases; D012333:RNA, Messenger; D051193:Toll-Like Receptors; C510646:ZC3H12A protein, human; C541320:Zc3h12a protein, mouse; D014157:Transcription Factors