title: Dual Role of Act1 in Keratinocyte Differentiation and Host Defense: TRAF3IP2 Silencing Alters Keratinocyte Differentiation and Inhibits IL-17 Responses.
abstract: TRAF3IP2 is a candidate psoriasis susceptibility gene encoding Act1, an adaptor protein with ubiquitin ligase activity that couples the IL-17 receptor to downstream signaling pathways. We investigated the role of Act1 in keratinocyte responses to IL-17 using a tetracycline inducible short hairpin RNA targeting TRAF3IP2. Tetracycline exposure for 7 days effectively silenced TRAF3IP2 mRNA and Act1 protein, resulting in 761 genes with significant changes in expression (495 down, 266 up; >1.5-fold, P < 0.05). Gene ontology analysis showed that genes affected by TRAF3IP2 silencing are involved in epidermal differentiation, with early differentiation genes (KRT1, KRT10, DSC1, DSG1) being down-regulated and late differentiation genes (SPRR2, SPRR3, LCE3) being up-regulated. AP1 binding sites were enriched upstream of genes up-regulated by TRAF3IP2 silencing. Correspondingly, nuclear expression of FosB and Fra1 was increased in TRAF3IP2-silenced cells. Many genes involved in host defense were induced by IL-17 in a TRAF3IP2-dependent fashion. Inflammatory differentiation conditions (serum addition for 4 days postconfluence) markedly amplified these IL-17 responses and increased basal levels and TRAF3IP2 silencing-dependent up-regulation of multiple late differentiation genes. These findings suggest that TRAF3IP2 may alter both epidermal homeostasis and keratinocyte defense responses to influence psoriasis risk.
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Sylviane
authors.initials: S
authors.lastname: Lambert
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA; Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Swindell
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA; Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Lam C
authors.initials: LC
authors.lastname: Tsoi
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Stoll
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA; Ann Arbor Veterans Affairs Health System, Ann Arbor, Michigan, USA. Electronic address: jelder@umich.edu.
authors.forename: James T
authors.initials: JT
authors.lastname: Elder
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D002454:Cell Differentiation; D002478:Cells, Cultured; D018031:Connexin 43 / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011565:Psoriasis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012313:RNA / Q000235:genetics*; D015398:Signal Transduction; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics*
chemical_list: C541130:ACT1 protein; D048868:Adaptor Proteins, Signal Transducing; D018031:Connexin 43; D020381:Interleukin-17; D010446:Peptide Fragments; C414202:TRAF3IP2 protein, human; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D012313:RNA