AP1S3 mutations are associated with pustular psoriasis and impaired toll-like receptor 3 trafficking

Niovi Setta-Kaffetzi, Michael A. Simpson, Alexander A. Navarini, Varsha M. Patel, Hui Chun Lu, Michael H. Allen, Michael Duckworth, Hervé Bachelez, A. David Burden, Siew Eng Choon, Christopher E M Griffiths, Brian Kirby, Antonios Kolios, Marieke M B Seyger, Christa Prins, Asma Smahi, Richard C. Trembath, Franca Fraternali, Catherine H. Smith, Jonathan N. BarkerFrancesca Capon

    Research output: Contribution to journalArticlepeer-review


    Adaptor protein complex 1 (AP-1) is an evolutionary conserved heterotetramer that promotes vesicular trafficking between the trans-Golgi network and the endosomes. The knockout of most murine AP-1 complex subunits is embryonically lethal, so the identification of human disease-associated alleles has the unique potential to deliver insights into gene function. Here, we report two founder mutations (c.11T>G [p.Phe4Cys] and c.97C>T [p.Arg33Trp]) in AP1S3, the gene encoding AP-1 complex subunit σ1C, in 15 unrelated individuals with a severe autoinflammatory skin disorder known as pustular psoriasis. Because the variants are predicted to destabilize the 3D structure of the AP-1 complex, we generated AP1S3-knockdown cell lines to investigate the consequences of AP-1 deficiency in skin keratinocytes. We found that AP1S3 silencing disrupted the endosomal translocation of the innate pattern-recognition receptor TLR-3 (Toll-like receptor 3) and resulted in a marked inhibition of downstream signaling. These findings identify pustular psoriasis as an autoinflammatory phenotype caused by defects in vesicular trafficking and demonstrate a requirement of AP-1 for Toll-like receptor homeostasis. © 2014 The American Society of Human Genetics.
    Original languageEnglish
    Pages (from-to)790-797
    Number of pages7
    JournalAmerican Journal of Human Genetics
    Issue number5
    Publication statusPublished - 1 May 2014


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