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.

Abstract

Cyclic adenosine monophosphate (cAMP) response element–binding protein (CREB)–binding protein (CBP) is a histone acetyltransferase that plays a pivotal role in the control of histone modification and the expression of cytokine-encoding genes in inflammatory diseases, including sepsis and lung injury. We found that the E3 ubiquitin ligase subunit FBXL19 targeted CBP for site-specific ubiquitylation and proteasomal degradation. The ubiquitylation-dependent degradation of CBP reduced the extent of lipopolysaccharide (LPS)–dependent histone acetylation and cytokine release in mouse lung epithelial cells and in a mouse model of sepsis. Furthermore, we demonstrated that the deubiquitylating enzyme USP14 (ubiquitin-specific peptidase 14) stabilized CBP by reducing its ubiquitylation. LPS increased the stability of CBP by reducing the association between CBP and FBXL19 and by activating USP14. Inhibition of USP14 reduced CBP protein abundance and attenuated LPS-stimulated histone acetylation and cytokine release. Together, our findings delineate the molecular mechanisms through which CBP stability is regulated by FBXL19 and USP14, which results in the modulation of chromatin remodeling and the expression of cytokine-encoding genes.

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