Oxidative, multistep activation of the noncanonical NF‐κB pathway via disulfide Bcl‐3/p50 complex

Buthionine sulfoximine (BSO) is a well‐known inhibitor of glutathione synthesis, producing slow glutathione (GSH) depletion and oxidative stress; some “responder” cells avoid BSO‐induced death by trans‐activating the prosurvival protein Bcl‐2. Here we show that BSO activates a noncanonical, inhibitory NF‐κB‐ and p65‐independent NF‐κB pathway via a multistep process leading to the up‐regulation of Bcl‐2. The slow BSO‐induced GSH depletion allows separation of two redox‐related phases, namely, early thiol disequilibrium and late frank oxidative stress;each phase contributes to the progressive activation of a p50‐p50 homodimer. The early phase, coinciding with substantial thiol depletion, produces a cytosolic prepar‐ative complex, consisting of p50 and its interactor Bcl‐3 linked by interprotein disulfide bridges. The late phase, coinciding with reactive oxygen species production, is responsible, probably via p38 activation, for nuclear targeting of the complex and frans‐activation of Bcl‐2.— Cristofanon, S., Morceau, F., Scovassi, A. I., Dicato, M., Ghibelli, L., Diederich, M. Oxidative, multistep activation of the noncanonical NF‐κB pathway via disulfide Bcl‐3/p50 complex. FASEBJ. 23, 45‐57 (2009)