Interleukin-1 (IL-1)-induced TAK1-dependent Versus MEKK3-dependent NFkappaB activation pathways bifurcate at IL-1 receptor-associated kinase modification.
Interleukin-1 (IL-1) receptor-associated kinase (IRAK) is phosphorylated after it is recruited to the receptor, subsequently ubiquitinated, and eventually degraded upon IL-1 stimulation. Although a point mutation changing lysine 134 to arginine (K134R) in IRAK abolished IL-1-induced IRAK ubiquitination and degradation, mutations of serines and threonines adjacent to lysine 134 to alanines ((S/T)A (131-144)) reduced IL-1-induced IRAK phosphorylation and abolished IRAK ubiquitination. Through the study of these IRAK modification mutants, we uncovered two parallel IL-1-mediated signaling pathways for NFkappaB activation, TAK1-dependent and MEKK3-dependent, respectively. These two pathways bifurcate at the level of IRAK modification. The TAK1-dependent pathway leads to IKKalpha/beta phosphorylation and IKKbeta activation, resulting in classical NFkappaB activation through IkappaBalpha phosphorylation and degradation. The TAK1-independent MEKK3-dependent pathway involves IKKgamma phosphorylation and IKKalpha activation, resulting in NFkappaB activation through IkappaBalpha phosphorylation and subsequent dissociation from NFkappaB but without IkappaBalpha degradation. These results provide significant insight to our further understanding of NFkappaB activation pathways.
Yao
Jianhong
J
Department of Immunology, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
Kim
Tae Whan
TW
Qin
Jinzhong
J
Jiang
Zhengfan
Z
Qian
Youcun
Y
Xiao
Hui
H
Lu
Yi
Y
Qian
Wen
W
Gulen
Muhammet Fatih
MF
Sizemore
Nywana
N
DiDonato
Joseph
J
Sato
Shintaro
S
Akira
Shizuo
S
Su
Bing
B
Li
Xiaoxia
X
D000818:Animals; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000378:metabolism*; D048748:MAP Kinase Kinase Kinase 3 / Q000502:physiology*; D020930:MAP Kinase Kinase Kinases / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000378:metabolism*; D017354:Point Mutation; D015398:Signal Transduction; D014162:Transfection; D000099151:MAP Kinase Kinase Kinase 7
D007375:Interleukin-1; D053592:Interleukin-1 Receptor-Associated Kinases; D048748:MAP Kinase Kinase Kinase 3; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D000099151:MAP Kinase Kinase Kinase 7; C482626:Map3k3 protein, mouse