Skin inflammation, a hallmark of psoriasis, has been the focus of study for many years. Tripartite motif-containing protein 21 (Trim21), which is an E3 ligase, is involved in mediating the inflammatory process and participates in the pathogenesis of various autoimmune diseases. We previously noticed that the expression of Trim21, which showed a significant 2. 6 ±0. 5 fold increase in mRNA level as well as an almost 3-fold increase in protein level (p<0. 05) in psoriasis epidermis as compared with normal skin, was markedly upregulated in psoriatic epidermis. Moreover, we proved that Trim21 was the main E3 ligase responsible for the ubiquitination of a marker of hyperproliferation-Keratin 17, which regulated its stability and its interaction with STAT3 in psoriatic keratinocytes. However, its role in mediating the inflammation, especially in keratinocytes, has not been elucidated. Herein, we illustrated a previously unrecognized role for Trim21 in promoting inflammation in keratinocytes, represented by stimulating the release of psoriasis-related cytokines and chemokines CXCL9-11, CCL20, IL-23 and IFN-γ. By screening a myriad of inflammation-related signaling pathways, we clarified that knockdown of Trim21 inhibited the activation of NF-κB and STAT3 pathways. Importantly, by immunoprecipitation combined with in vitro ubiquitination assays, we found that Trim21 interacted with and ubiquitylated p65 subunit of NF-κB, which further enhanced p65 phosphorylation and activation by IKK, initiating expression of the aforementioned downstream cytokines and chemokines. Lastly, in vivo studies showed that knockdown of Trim21 had a satisfactory effect in alleviating the imiquimod (IMQ)-induced psoriasiform lesions. Our present study uncovers a pivotal role of Trim21 in promoting inflammation in psoriatic keratinocytes, which might contribute to the pathogenesis of psoriasis. Thus, Trim21 might be a potential target for the treatment of psoriasis.

E3 ligase Trim21 ubiquitylates NF-κB p65 subunit and promotes inflammation in psoriatic keratinocytes