AP1S3 mutations are associated with pustular Psoriasis and Impaired Toll-like Receptor 3 Trafficking

Setta-Kaffetzi, N. et al. (2014) AP1S3 mutations are associated with pustular Psoriasis and Impaired Toll-like Receptor 3 Trafficking. American Journal of Human Genetics, 94(5), pp. 790-797. (doi: 10.1016/j.ajhg.2014.04.005)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Burden, Professor David
• Authors: Setta-Kaffetzi, N., Simpson, M. A., Navarini, A. A., Patel, V. M., Lu, H.-C., Allen, M. H., Duckworth, M., Bachelez, H., Burden, A. D., Choon, S.-E., Griffiths, C. E.M., Kirby, B., Kolios, A., Seyger, M. M.B., Prins, C., Smahi, A., Trembath, R. C., Fraternali, F., Smith, C. H., Barker, J. N., and Capon, F.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: American Journal of Human Genetics
• Publisher: Cell Press
• ISSN: 0002-9297
• ISSN (Online): 1537-6605