Regulation of the psoriatic chemokine CCL20 by E3 ligases Trim32 and Piasy in keratinocytes.
Psoriasis is an inflammatory skin disorder with aberrant regulation of keratinocytes and immunocytes. Although it is well known that uncontrolled keratinocyte proliferation is largely driven by proinflammatory cytokines from the immunocytes, the functional role of keratinocytes in the regulation of immunocytes is poorly understood. Recently, we found that tripartite motif-containing protein 32 (Trim32), an E3-ubiquitin ligase, is elevated in the epidermal lesions of human psoriasis. We previously showed that Trim32 binds to the protein inhibitor of activated STAT-Y (Piasy) and mediates its degradation through ubiquitination. Interestingly, the Piasy gene is localized in the PSORS6 susceptibility locus on chromosome 19p13, and Piasy negatively regulates the activities of several transcription factors, including NF-kappaB, STAT, and SMADs, that are implicated in the pathogenesis of psoriasis. In this study, we show that Trim32 activates, and Piasy inhibits, keratinocyte production of CC chemokine ligand 20 (CCL20), a psoriatic chemokine essential for recruitment of DCs and T helper (Th)17 cells to the skin. Further, Trim32/Piasy regulation of CCL20 is mediated through Piasy interaction with the RelA/p65 subunit of NF-kappaB. As CCL20 is activated by Th17 cytokines, the upregulation of CCL20 production by Trim32 provides a positive feedback loop of CCL20 and Th17 activation in the self-perpetuating cycle of psoriasis.
Liu
Yuangang
Y
Department of Dermatology, Oregon Health & Science University, Portland, Oregon, USA. liuy@ohsu.ed
Lagowski
James P
JP
Gao
Shangpu
S
Raymond
James H
JH
White
Clifton R
CR
Kulesz-Martin
Molly F
MF
D000818:Animals; D002460:Cell Line; D054418:Chemokine CCL20 / Q000235:genetics / Q000378:metabolism*; D004817:Epidermis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D000075223:Poly-ADP-Ribose Binding Proteins; D050828:Protein Inhibitors of Activated STAT / Q000235:genetics / Q000378:metabolism*; D011565:Psoriasis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051996:Transcription Factor RelA / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D000070584:Tripartite Motif Proteins; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology
C108355:CCL20 protein, human; C493447:CCL20 protein, mouse; D054418:Chemokine CCL20; D020381:Interleukin-17; C485891:PIAS4 protein, human; C414349:Piasy protein, mouse; D000075223:Poly-ADP-Ribose Binding Proteins; D050828:Protein Inhibitors of Activated STAT; C498143:RELA protein, human; D051996:Transcription Factor RelA; D014157:Transcription Factors; D000070584:Tripartite Motif Proteins; D014409:Tumor Necrosis Factor-alpha; C094027:TRIM32 protein, human; C514011:TRIM32 protein, mouse; D044767:Ubiquitin-Protein Ligases