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

  • Author Footnotes
    1 These authors contributed equally to the work.
    Jie Zhang
    Footnotes
    1 These authors contributed equally to the work.
    Affiliations
    Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University, Xi’an, China
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  • Author Footnotes
    1 These authors contributed equally to the work.
    Jiuling Zhu
    Footnotes
    1 These authors contributed equally to the work.
    Affiliations
    Laboratory of Gene Therapy, Department of Biochemistry, College of Life Sciences, Shaanxi Normal University, Xi’an, China
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  • Xiaowen Chen
    Affiliations
    Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University, Xi’an, China
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  • Haibin Xia
    Correspondence
    Corresponding authors.
    Affiliations
    Laboratory of Gene Therapy, Department of Biochemistry, College of Life Sciences, Shaanxi Normal University, Xi’an, China
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  • Luting Yang
    Correspondence
    Corresponding authors.
    Affiliations
    Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University, Xi’an, China
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to the work.
Published:September 06, 2022DOI:https://doi.org/10.1016/j.jdermsci.2022.09.002

      Highlights

      • Keratinocyte secretes a wide variety of cytokines and chemokines to amplify the inflammatory responses in psoriasis.
      • Trim33 functions as an E3 ligase and mediates ubiquitination process.
      • Anxa2, a positive regulator of NF-κB pathway, is a newly recognized substrate of Trim33 in keratinocytes.
      • Trim33 ubiquitylates Anxa2 and promotes inflammation in keratinocytes via Anxa2/ NF-κB pathway.

      Abstract

      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.

      Key words

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