TY - JOUR
T1 - Regulation of the psoriatic chemokine CCL20 by E3 ligases trim32 and piasy in keratinocytes
AU - Liu, Yuangang
AU - Lagowski, James P.
AU - Gao, Shangpu
AU - Raymond, James H.
AU - White, Clifton R.
AU - Kulesz-Martin, Molly F.
N1 - Funding Information:
We thank Hao Ding for providing Trim32-null mice, Mihail Iordanov for providing the human keratinocyte HEKnV, Susan Lillie for providing clinical specimens, Carolyn Gendron and the Knight Pathology Core for assistance in histology, Knight DNA Sequencing & Synthesis Core Lab for oligo synthesis, Erin Harper for CCL20 qPCR assistance, and Andrew Blauvelt for helpful discussion. This study was supported by a National Psoriasis Foundation research grant to Yuangang Liu, 2007–08 OHSU Presidential Bridge Funding, Knight Cancer Institute Core grant CA69533, NIH CA98577, and NIH AR55651.
PY - 2010/5
Y1 - 2010/5
N2 - 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-B, 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-B. 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.
AB - 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-B, 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-B. 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.
UR - http://www.scopus.com/inward/record.url?scp=77951093007&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77951093007&partnerID=8YFLogxK
U2 - 10.1038/jid.2009.416
DO - 10.1038/jid.2009.416
M3 - Article
C2 - 20054338
AN - SCOPUS:77951093007
SN - 0022-202X
VL - 130
SP - 1384
EP - 1390
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
IS - 5
ER -