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

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2015-04

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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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10.1038/jid.2014.519

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Zhang, Xiaoling, Jane Y Jin, Joseph Wu, Xiaoxia Qin, Robert Streilein, Russell P Hall and Jennifer Y Zhang (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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Hall

Russell P. Hall

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 of this disease. Studies are currently focused on understanding the systemic manifestations of the mucosal immune response to dietary ingestion of wheat proteins in patients with DH. Studies are directed at determining the pattern of cytokine activation and inflammatory cell activation in the gut, skin and circulation. These studies are focused on understanding the manner in which gastrointestinal inflammation leads to the development of skin lesions in patients with DH and will provide new insight into the pathogenesis of the numerous skin diseases associated with inflammatory gastrointestinal disease.
In addition, our laboratory is investigating the pathogenesis of the organ specific auto immune blistering diseases bullous pemphigoid, and pemphigus vulgaris. These studies are directed at understanding auto-antibody epitopes and their relationship to disease activity and the role of B cells in the development and maintaince of auto-antibodies. Clinical trials are ongoing in both pemphigus and bullous pemphigoid that are coupled with mechanistic studies.

Zhang

Jennifer Yunyan Zhang

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 differentiation

Using regenerated human skin tissues and murine genetic models, we have demonstrated important functions NF-kB and AP-1 gene regulators in epidermal cell growth and differentiation. Currently, our efforts are focused on understating how loss-of-function of CYLD, a deubiquitinase and tumor suppressor, leads to the development of hair follicle defects, skin inflammation, and cancer. Specifically, we want to determine how CYLD integrates NF-kB, AP1, Myc, and other transcription factors to control epidermal cell growth and lineage differentiation.

De novo skin regeneration is life-saving procedure for severely burned patients and lethal genetic skin diseases such as epidermal bullosa. An additional aspect of our study is to improve new skin regeneration techniques and to create experimental skin disease models with gene transduced keratinocytes, as illustrated below.

2. Keratinocytes as instigators of inflammatory responses

Keratinocytes are constantly challenged by external insults, as well as immune cells. Disarray of the crosstalk between keratinocytes and immune cells underlies various immune diseases, including dermatitis, psoriasis, and cutaneous graft-versus-host disease (GVHD). GVHD is a common complication and the leading cause of non-relapse mortality among patients after receiving allogenic hematopoietic stem cell transplantation.  The skin is the most commonly affected organ in both the acute and chronic forms of this disease.  Treatment options for GVHD are limited and the current standard therapy is high dose systemic corticosteroid which is itself associated with significant morbidity. Our goal is to understand how keratinocytes contribute to the progression of GVHD, and may therefore be targeted to mitigate the disease.

3. Ubiquitination enzymes in melanoma

Melanoma most lethal and difficult to treat skin cancer. In the recent years, BRAF/MEK-targeted therapies have produced exciting results, but they suffer from short duration. Our goal is to uncover novel mechanisms crucial for melanoma malignancy. Specifically, we want to understand how ubiquitination enzymes contribute to melanoma growth. Previously, we have demonstrated that CYLD inhibits melanoma growth through suppression of JNK/AP1 and b1-integrin signaling pathways. In contrast, UBE2N, a K63-Ubiquitin conjusage, promotes melanoma growth in part through activation of the MEK/FRA/SOX10 signaling cascade. Currently, our efforts are focused on understanding how UBE2N and other ubiquitin enzymes regulate the MAPK signaling pathway and whether they can be targeted for melanoma therapy.


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