Research ArticleImmunology

Regulation of the ubiquitylation and deubiquitylation of CREB-binding protein modulates histone acetylation and lung inflammation

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Sci. Signal.  13 Jun 2017:
Vol. 10, Issue 483, eaak9660
DOI: 10.1126/scisignal.aak9660

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Targeting CBP stability

Acetylation of histone H4 by the histone acetyltransferase CBP during sepsis switches chromatin to an open state, which enables the expression of genes encoding proinflammatory cytokines. Understanding the regulation of CBP stability could help in the treatment of inflammatory diseases. Wei et al. showed that the E3 ubiquitin ligase subunit FBXL19 ubiquitylated CBP, targeting it for proteasomal degradation. The authors also showed that the deubiquitylase USP14 reversed this process, enhancing CBP stability. Furthermore, signaling by the bacterial product LPS prevented the FBXL19-CBP interaction and enhanced USP14 activity, thus promoting inflammatory cytokine production. Pharmacological inhibition of USP14 led to reduced CBP abundance and decreased cytokine production, suggesting that manipulation of CBP stability may provide a means to control inflammatory responses to infections.