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

Authors
Type
Published Article
Journal
The FASEB Journal
Publisher
Federation of American Society for Experimental Biology
Publication Date
Sep 15, 2008
Volume
23
Issue
1
Pages
57–57
Identifiers
DOI: 10.1096/fj.07-104109
Source
LBMCC
Keywords
License
Yellow

Abstract

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-kappaB- and p65-independent NF-kappaB 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 preparative 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 trans-activation of Bcl-2.

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