| Accession |
PRJCA003357 |
| Title |
DDX5-sIL-36R in keratinocytes controls skin inflammation |
| Relevance |
Medical |
| Data types |
Transcriptome or Gene expression
|
| Organisms |
Mus musculus
Homo sapiens
|
| Description |
The DEAD-box (DDX) proteins function in diverse cellular processes including RNA alternative splicing, and are linked to immune-mediated diseases. However, little is known about the roles of DDXs in skin inflammatory diseases. Here, we show that DDX5, one of the founding members of the DDX RNA helicase family, controls skin inflammation and participates in the pathogenesis of psoriasis via regulating IL-36R pre-mRNA splicing. We found that both mRNA and protein of DDX5 are decreased in lesional skin from patients with psoriasis and psoriasis-like mice, and that mice with keratinocyte-specific ablation of DDX5 spontaneously develop psoriasis-like phenotypes. Mechanistically, DDX5 complexes with serine/arginine-rich splicing factor 1(SRSF1) to typically regulate IL-36R pre-mRNA splicing in keratinocytes, which generates mRNAs encoding full-length IL-36R and a previously unknown soluble form of IL-36R (sIL-36R). sIL-36R controls IL-36/IL-36R signaling by competing with IL-36R for IL-36γ ligation. The reduction or deficiency of DDX5 leads to IL-36R pre-mRNA splicing preferring to the generation of IL-36R but not sIL-36R, thereby selectively amplifying inflammatory responses of keratinocytes to IL-36γ and then aggravating cutaneous inflammation in psoriasis. Genetic restoration or intradermal administration of sIL-36R in psoriasis-like mice suppresses IL-36R signaling and alleviates the disease phenotype of psoriasis. Altogether, these data reveal a pathogenic role of DDX5 during psoriasis, and provide mechanistic insights into the regulation of IL-36R splicing and its impact on psoriasis development. |
| Sample scope |
Multiisolate |
| Release date |
2022-06-09 |
| Grants |
| Agency |
program |
Grant ID |
Grant title |
| National Key Research and Development Program of China
|
|
2016YFC0906200
|
|
| National Key Research and Development Program of China
|
|
2016YFC0906202
|
|
| National Natural Science Foundation of China (NSFC)
|
|
31670925
|
|
| National Natural Science Foundation of China (NSFC)
|
|
31470878
|
|
|
|
| Submitter |
Yuping
Lai (yplai@bio.ecnu.edu.cn)
|
| Organization |
East China Normal University |
| Submission date |
2020-08-31 |
