eIF2α-Independent Inhibition of TNF-α-Triggered NF-κB Activation by Salubrinal.
Salubrinal is a selective inhibitor of cellular complexes that dephosphorylate eukaryotic translation initiation factor 2α (eIF2α). In previous reports, salubrinal was shown to have the potential to inhibit the activation of nuclear factor-κB (NF-κB) by several stimuli. However, the effects of salubrinal on NF-κB signaling are largely unknown. In this study, we investigated whether and how salubrinal affects NF-κB activation induced by tumor necrosis factor (TNF)-α and interleukin (IL)-1β. We found that salubrinal selectively blocked TNF-α- but not IL-1β-induced activation of NF-κB. This inhibitory effect occurred upstream of transforming growth factor (TGF)-β-activated kinase 1 (TAK1). Further experiments revealed that salubrinal blocked TNF-α-triggered NF-κB activation independent of its action on eIF2α because knockdown of eIF2α by small interfering RNA (siRNA) did not reverse the inhibitory effect of salubrinal on NF-κB. Moreover, guanabenz, a selective inhibitor of the regulatory subunit of protein phosphatase (PP) 1, also preferentially inhibited TNF-α-triggered activation of NF-κB. These findings raise the possibility that salubrinal may selectively block TNF-α-triggered activation of the NF-κB pathway through inhibition of the PP1 complex.
Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi.
Shotaro
S
Nakajima
Yuan
Y
Chi
Kun
K
Gao
Koji
K
Kono
Jian
J
Yao
D000818:Animals; D002460:Cell Line; D002934:Cinnamates / Q000494:pharmacology*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D006143:Guanabenz / Q000494:pharmacology; D053583:Interleukin-1beta / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D051381:Rats; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D002934:Cinnamates; D015852:Eukaryotic Initiation Factor-2; D053583:Interleukin-1beta; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C496827:salubrinal; D006143:Guanabenz; D013890:Thiourea