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

• Published in: American journal of human genetics 2014-05, Vol.94 (5), p.790-797
• Main Authors: Setta-Kaffetzi, Niovi, Simpson, Michael A., Navarini, Alexander A., Patel, Varsha M., Lu, Hui-Chun, Allen, Michael H., Duckworth, Michael, Bachelez, Hervé, Burden, A. David, Choon, Siew-Eng, Griffiths, Christopher E.M., Kirby, Brian, Kolios, Antonios, Seyger, Marieke M.B., Prins, Christa, Smahi, Asma, Trembath, Richard C., Fraternali, Franca, Smith, Catherine H., Barker, Jonathan N., Capon, Francesca
• Format: Article
• Language: English
• Subjects: Adaptor Protein Complex 1 - chemistry; Adaptor Protein Complex 1 - genetics; Amino Acid Sequence; Amino Acid Substitution; Cell Line; Female; Gene Knockdown Techniques; Genotype & phenotype; Homeostasis; Humans; Male; Molecular Sequence Data; Mutation; Protein Conformation; Protein Transport - genetics; Proteins; Psoriasis; Psoriasis - genetics; Psoriasis - metabolism; Toll-Like Receptor 3 - metabolism
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1016/j.ajhg.2014.04.005

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.