title: AP1S3 mutations are associated with pustular psoriasis and impaired Toll-like receptor 3 trafficking.
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.
authors.affiliation: Division of Genetics and Molecular Medicine, King's College London, London SE1 9RT, UK.
authors.forename: Niovi
authors.initials: N
authors.lastname: Setta-Kaffetzi
authors.affiliation: Division of Genetics and Molecular Medicine, King's College London, London SE1 9RT, UK.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Simpson
authors.affiliation: Division of Genetics and Molecular Medicine, King's College London, London SE1 9RT, UK.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Navarini
authors.affiliation: Division of Genetics and Molecular Medicine, King's College London, London SE1 9RT, UK.
authors.forename: Varsha M
authors.initials: VM
authors.lastname: Patel
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, London SE1 9RT, UK.
authors.forename: Hui-Chun
authors.initials: HC
authors.lastname: Lu
authors.affiliation: Division of Genetics and Molecular Medicine, King's College London, London SE1 9RT, UK.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Allen
authors.affiliation: Division of Genetics and Molecular Medicine, King's College London, London SE1 9RT, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Duckworth
authors.affiliation: Institut National de la Santé et de la Recherche Médicale Unité 781, Institut Imagine, Hopital Necker - Enfant Malades, Paris 75015, France; Department of Dermatology, Sorbonne Paris Cité Université Paris Diderot and Hôpital Saint-Louis, Assistance Publique - Hôpitaux de Paris, Paris 75010, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Bachelez
authors.affiliation: Department of Dermatology, University of Glasgow, Glasgow G11 6NT, UK.
authors.forename: A David
authors.initials: AD
authors.lastname: Burden
authors.affiliation: Department of Dermatology, Hospital Sultanah Aminah, Johor Bahru 80100, Malaysia.
authors.forename: Siew-Eng
authors.initials: SE
authors.lastname: Choon
authors.affiliation: Department of Dermatology, University of Manchester, Manchester M6 8HD, UK.
authors.forename: Christopher E M
authors.initials: CE
authors.lastname: Griffiths
authors.affiliation: Department of Dermatology, St. Vincent University Hospital, Dublin 4, Ireland.
authors.forename: Brian
authors.initials: B
authors.lastname: Kirby
authors.affiliation: Department of Dermatology, Zurich University Hospital, Zurich 8091, Switzerland.
authors.forename: Antonios
authors.initials: A
authors.lastname: Kolios
authors.affiliation: Department of Dermatology, Radboud University Nijmegen Medical Centre, 6500HB Nijmegen, the Netherlands.
authors.forename: Marieke M B
authors.initials: MM
authors.lastname: Seyger
authors.affiliation: Dermatology Service, Geneva University Hospital, 1211 Geneva 14, Switzerland.
authors.forename: Christa
authors.initials: C
authors.lastname: Prins
authors.affiliation: Institut National de la Santé et de la Recherche Médicale Unité 781, Institut Imagine, Hopital Necker - Enfant Malades, Paris 75015, France.
authors.forename: Asma
authors.initials: A
authors.lastname: Smahi
authors.affiliation: Division of Genetics and Molecular Medicine, King's College London, London SE1 9RT, UK; Queen Mary University of London, Barts and The London School of Medicine and Dentistry, London EC1M 6QB, UK.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Trembath
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, London SE1 9RT, UK.
authors.forename: Franca
authors.initials: F
authors.lastname: Fraternali
authors.affiliation: Division of Genetics and Molecular Medicine, King's College London, London SE1 9RT, UK.
authors.forename: Catherine H
authors.initials: CH
authors.lastname: Smith
authors.affiliation: Division of Genetics and Molecular Medicine, King's College London, London SE1 9RT, UK.
authors.forename: Jonathan N
authors.initials: JN
authors.lastname: Barker
authors.affiliation: Division of Genetics and Molecular Medicine, King's College London, London SE1 9RT, UK. Electronic address: francesca.capon@kcl.ac.uk.
authors.forename: Francesca
authors.initials: F
authors.lastname: Capon
mesh_terms: D033961:Adaptor Protein Complex 1 / Q000737:chemistry / Q000235:genetics*; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D002460:Cell Line; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D011487:Protein Conformation; D021381:Protein Transport / Q000235:genetics; D011565:Psoriasis / Q000235:genetics* / Q000378:metabolism*; D051196:Toll-Like Receptor 3 / Q000378:metabolism*
chemical_list: D033961:Adaptor Protein Complex 1; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3