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 journalArticleResearchpeer-review

82 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)790-797
Number of pages8
JournalAmerican Journal of Human Genetics
Volume94
Issue number5
DOIs
Publication statusPublished - 1 May 2014
Externally publishedYes

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