RNA-Seq and ChIP-Seq reveal SQSTM1/p62 as a key mediator of JunB suppression of NF-κB-dependent inflammation.
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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.
SubjectAdaptor Proteins, Signal Transducing
Oligonucleotide Array Sequence Analysis
Sequence Analysis, RNA
Skin Physiological Phenomena
Published Version (Please cite this version)10.1038/jid.2014.519
Publication InfoZhang, Xiaoling; Jin, Jane Y; Wu, Joseph; Qin, Xiaoxia; Streilein, Robert; Hall, Russell P; & Zhang, Jennifer Y (2015). RNA-Seq and ChIP-Seq reveal SQSTM1/p62 as a key mediator of JunB suppression of NF-κB-dependent inflammation. J Invest Dermatol, 135(4). pp. 1016-1024. 10.1038/jid.2014.519. Retrieved from https://hdl.handle.net/10161/15166.
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J. Lamar Callaway Distinguished Professor of Dermatology, in the School of Medicine
Our laboratory is investigating the pathogenesis of autoimmune blistering skin diseases. Areas of special expertise include immune mediated skin diseases, especially immune mediated primary blistering disorders. These include pathogenesis, diagnosis, and management. Specifically our laboratory is investigating the role of the mucosal immune response in the pathogenesis of dermatitis herpetiformis (DH) and the role the associated gluten sensitive enteropathy (GSE) plays in the development o
Associate Professor in Dermatology
Epidermis of the skin constitutes the largest organ and the outer most barrier of the body. It is one of the few organs that undergo lifelong self-renewal through a tight balance of cell growth, differentiation, and programmed cell death. Deregulation of this balance is manifested in many diseases, including various immune diseases and cancer. Our lab is focused on 3 interrelated topics: 1. Gene regulation of epithelial cell proliferation and differenti
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