Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 94, Issue 5, Pages 790-797Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2014.04.005
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Funding
- Department of Health via the National Institute for Health Research BioResource Clinical Research Facility and comprehensive Biomedical Research Centre
- King's College London
- Lung GO Sequencing Project [HL-102923]
- Women's Health Initiative Sequencing Project [HL-102924]
- Broad GO Sequencing Project [HL-102925]
- Seattle GO Sequencing Project [HL-102926]
- Heart GO Sequencing Project [HL-103010]
- National Psoriasis Foundation
- Wellcome Trust
- European Commission
- British Skin Foundation [3007s]
- Swiss National Science Foundation [PASMP3_140074/WGS]
- King's College Hospital NHS Foundation Trust
- BBSRC [BB/I023291/1] Funding Source: UKRI
- MRC [MR/L01257X/1] Funding Source: UKRI
- Swiss National Science Foundation (SNF) [PASMP3_140074] Funding Source: Swiss National Science Foundation (SNF)
- Biotechnology and Biological Sciences Research Council [BB/I023291/1] Funding Source: researchfish
- Medical Research Council [MR/L01257X/1] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0507-10379] Funding Source: researchfish
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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 sigma 1C, 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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