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RNA-Seq and ChIP-Seq reveal SQSTM1/p62 as a key mediator of JunB suppression of NF-κB-dependent inflammation.

Zhang X, Jin JY, Wu J, Qin X, Streilein R, Hall RP, Zhang JY - J. Invest. Dermatol. (2014)

Bottom Line: Here we demonstrate that impaired JunB function via gene silencing or overexpression of a dominant negative mutant increased human keratinocyte cell proliferation but decreased cell barrier function.Conversely, NF-κB inhibition genetically with a mutant IκBα or pharmacologically with pyrrolidine dithiocarbamate (PDTC) prevented cytokine, but not IL6R, induction by JunB deficiency.Taken together, our findings indicate that JunB controls epidermal growth, barrier formation, and proinflammatory responses through direct and indirect mechanisms, pinpointing SQSTM1 as a key mediator of JunB suppression of NF-κB-dependent inflammation.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, Duke University, Durham, North Carolina, USA.

ABSTRACT
Mice with epidermal deletion of JunB transcription factor displayed a psoriasis-like inflammation. The relevance of these findings to humans and the mechanisms mediating JunB function are not fully understood. Here we demonstrate that impaired JunB function via gene silencing or overexpression of a dominant negative mutant increased human keratinocyte cell proliferation but decreased cell barrier function. RNA-seq revealed over 500 genes affected by JunB loss of function, which included the upregulation of an array of proinflammatory molecules relevant to psoriasis. Among these were tumor necrosis factor α (TNFα), CCL2, CXCL10, IL6R, and SQSTM1, an adaptor protein involved in nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation. Chromatin immunoprecipitation (ChIP)-Seq and gene reporter analyses showed that JunB directly suppressed SQSTM1 by binding to a consensus AP-1 cis element located around 2 kb upstream of SQSTM1-transcription start site. Similar to JunB loss of function, SQSTM1-overexpression induced TNFα, CCL2, and CXCL10. Conversely, NF-κB inhibition genetically with a mutant IκBα or pharmacologically with pyrrolidine dithiocarbamate (PDTC) prevented cytokine, but not IL6R, induction by JunB deficiency. Taken together, our findings indicate that JunB controls epidermal growth, barrier formation, and proinflammatory responses through direct and indirect mechanisms, pinpointing SQSTM1 as a key mediator of JunB suppression of NF-κB-dependent inflammation.

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Working modelJunB-suppression of inflammation. JunB regulates epidermal cell proliferation, cell adhesion and inflammation through direct and indirect target genes. In particular, JunB-hypofunction leads to increased expression of SQSTM1 and consequently NF-κB-dependent expression of multiple inflammatory cytokines.
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Figure 6: Working modelJunB-suppression of inflammation. JunB regulates epidermal cell proliferation, cell adhesion and inflammation through direct and indirect target genes. In particular, JunB-hypofunction leads to increased expression of SQSTM1 and consequently NF-κB-dependent expression of multiple inflammatory cytokines.

Mentions: Taken together, our findings support a working model in which JunB-hypofunction leads to increased expression of SQSTM1 and consequent NF-κB-dependent induction of proinflammatory cytokines (Fig. 6). Additionally, JunB loss-of-function increases cell proliferation, and compromises barrier functions through direct and indirect target gene regulations. Future studies are needed to determine whether the proinflammatory cytokines indirectly affect cell growth and barrier function.


RNA-Seq and ChIP-Seq reveal SQSTM1/p62 as a key mediator of JunB suppression of NF-κB-dependent inflammation.

Zhang X, Jin JY, Wu J, Qin X, Streilein R, Hall RP, Zhang JY - J. Invest. Dermatol. (2014)

Working modelJunB-suppression of inflammation. JunB regulates epidermal cell proliferation, cell adhesion and inflammation through direct and indirect target genes. In particular, JunB-hypofunction leads to increased expression of SQSTM1 and consequently NF-κB-dependent expression of multiple inflammatory cytokines.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4366298&req=5

Figure 6: Working modelJunB-suppression of inflammation. JunB regulates epidermal cell proliferation, cell adhesion and inflammation through direct and indirect target genes. In particular, JunB-hypofunction leads to increased expression of SQSTM1 and consequently NF-κB-dependent expression of multiple inflammatory cytokines.
Mentions: Taken together, our findings support a working model in which JunB-hypofunction leads to increased expression of SQSTM1 and consequent NF-κB-dependent induction of proinflammatory cytokines (Fig. 6). Additionally, JunB loss-of-function increases cell proliferation, and compromises barrier functions through direct and indirect target gene regulations. Future studies are needed to determine whether the proinflammatory cytokines indirectly affect cell growth and barrier function.

Bottom Line: Here we demonstrate that impaired JunB function via gene silencing or overexpression of a dominant negative mutant increased human keratinocyte cell proliferation but decreased cell barrier function.Conversely, NF-κB inhibition genetically with a mutant IκBα or pharmacologically with pyrrolidine dithiocarbamate (PDTC) prevented cytokine, but not IL6R, induction by JunB deficiency.Taken together, our findings indicate that JunB controls epidermal growth, barrier formation, and proinflammatory responses through direct and indirect mechanisms, pinpointing SQSTM1 as a key mediator of JunB suppression of NF-κB-dependent inflammation.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, Duke University, Durham, North Carolina, USA.

ABSTRACT
Mice with epidermal deletion of JunB transcription factor displayed a psoriasis-like inflammation. The relevance of these findings to humans and the mechanisms mediating JunB function are not fully understood. Here we demonstrate that impaired JunB function via gene silencing or overexpression of a dominant negative mutant increased human keratinocyte cell proliferation but decreased cell barrier function. RNA-seq revealed over 500 genes affected by JunB loss of function, which included the upregulation of an array of proinflammatory molecules relevant to psoriasis. Among these were tumor necrosis factor α (TNFα), CCL2, CXCL10, IL6R, and SQSTM1, an adaptor protein involved in nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation. Chromatin immunoprecipitation (ChIP)-Seq and gene reporter analyses showed that JunB directly suppressed SQSTM1 by binding to a consensus AP-1 cis element located around 2 kb upstream of SQSTM1-transcription start site. Similar to JunB loss of function, SQSTM1-overexpression induced TNFα, CCL2, and CXCL10. Conversely, NF-κB inhibition genetically with a mutant IκBα or pharmacologically with pyrrolidine dithiocarbamate (PDTC) prevented cytokine, but not IL6R, induction by JunB deficiency. Taken together, our findings indicate that JunB controls epidermal growth, barrier formation, and proinflammatory responses through direct and indirect mechanisms, pinpointing SQSTM1 as a key mediator of JunB suppression of NF-κB-dependent inflammation.

Show MeSH
Related in: MedlinePlus