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AP1S3 Mutations Are Associated with Pustular Psoriasis and Impaired Toll-like Receptor 3 Trafficking

Research output: Contribution to journalArticle

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 Barker & 1 more Francesca Capon

Original languageEnglish
Pages (from-to)790-797
Number of pages8
JournalAmerican Journal of Human Genetics
Volume94
Issue number5
Early online date5 May 2014
DOIs
Publication statusPublished - May 2014

King's Authors

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.

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