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

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

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Official URL: https://edoc.unibas.ch/76685/

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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.
Faculties and Departments:03 Faculty of Medicine > Bereich Spezialfächer (Klinik) > Dermatologie USB > Dermatologie (Navarini)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Spezialfächer (Klinik) > Dermatologie USB > Dermatologie (Navarini)
UniBasel Contributors:Navarini, Alexander
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Univ. of Chicago Press
ISSN:0002-9297
e-ISSN:1537-6605
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:01 Jun 2020 07:56
Deposited On:01 Jun 2020 07:56

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