SCF(Fbw7) modulates the NFkB signaling pathway by targeting NFkB2 for ubiquitination and destruction.
The NFkB/Rel family of proteins play critical roles in a variety of cellular processes. Thus, their physiological activation is tightly controlled. Recently, the NFkB2/p100 precursor has been characterized as the fourth IkB type of suppressor for NFkB. However, the molecular mechanism(s) underlying regulated destruction of NFkB2 remains largely unknown. Here, we report that, unlike other IkBs, ubiquitination and destruction of NFkB2 are governed by SCF(Fbw7) in a GSK3-dependent manner. In Fbw(7-/-) cells, elevated expression of NFkB2/p100 leads to a subsequent reduction in NFkB signaling pathways and elevated sensitivity to TNFa-induced cell death. Reintroducing wild-type Fbw7, but not disease-derived mutant forms of Fbw7, rescues NFkB activity. Furthermore, T cell-specific depletion of Fbw7 also leads to reduced NFkB activity and perturbed T cell differentiation. Therefore, our work identifies Fbw7 as a physiological E3 ligase controlling NFkB20s stability. It further implicates that Fbw7 might exert its tumor-suppressor function by regulating NFkB activity.
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Hidefumi
H
Fukushima
Akinobu
A
Matsumoto
Hiroyuki
H
Inuzuka
Bo
B
Zhai
Alan W
AW
Lau
Lixin
L
Wan
Daming
D
Gao
Shavali
S
Shaik
Min
M
Yuan
Steven P
SP
Gygi
Eijiro
E
Jimi
John M
JM
Asara
Keiko
K
Nakayama
Keiichi I
KI
Nakayama
Wenyi
W
Wei
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000595:Amino Acid Sequence; D000818:Animals; D018797:Cell Cycle Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism*; D052003:NF-kappa B p52 Subunit / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology*
D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; C513272:Fbxw7 protein, mouse; D016328:NF-kappa B; D052003:NF-kappa B p52 Subunit; C498207:Nfkb2 protein, mouse; D044767:Ubiquitin-Protein Ligases; D038362:Glycogen Synthase Kinase 3