E3 ubiquitin ligase Trim33 ubiquitylates Annexin A2 to promote NF-κB induced skin inflammation in psoriasis

Background: Tripartite motif-containing protein 33, a member of the TRIM E3 ligase family, is shown to be involved in tumorigenesis, cell proliferation and inflammation. Alteration of several TRIM family proteins in psoriatic epidermis has been shown to participate in psoriasis pathogenesis. However, little is known about Trim33 expression and its role in psoriasis.

Objectives: To examine the expression and biological roles of Trim33 in psoriatic process, with a focus on identifying its novel substrates in psoriatic keratinocytes.

Methods: Gene expression of Trim33 in biopsies from psoriasis patients compared with healthy volunteers was analysed by quantitative real-time polymerase chain reaction (qPCR) and immunofluorescence (IF). Identification of Trim33 substrates were performed using immunoprecipitation combined with mass spectrometry. Protein expression and localization were assessed by immunoblotting and immunofluorescence. Expression of cytokines was analysed with qPCR.

Results: qPCR and IF analysis revealed increased expression of Trim33 in psoriatic epidermis. Overexpression of Trim33 promoted the expression of psoriasis-related proinflammatory cytokines IL-6, IL-1β and NLRP3 inflammasome. Intriguingly, Trim33 induced lysine 63 (K63)-linked ubiquitination of Annexin A2 (Anxa2), which promoted its interaction with p50/p65 subunits of NF-κB, favoured the retention of p50/p65 in the nucleus and promoted the expression of inflammation-related NF-κB downstream genes.

Conclusions: Our study highlights the upregulation of Trim33 in psoriatic epidermis and its pivotal role in promoting the inflammation of keratinocytes by Anxa2/NF-κB pathway. Our findings imply that Trim33 might be further explored as potential target for psoriasis treatment.