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AP1S3 mutations are associated with pustular psoriasis and impaired Toll-like receptor 3 trafficking.
- Source :
-
American journal of human genetics [Am J Hum Genet] 2014 May 01; Vol. 94 (5), pp. 790-7. - Publication Year :
- 2014
-
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.<br /> (Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Adaptor Protein Complex 1 chemistry
Amino Acid Sequence
Amino Acid Substitution
Cell Line
Female
Gene Knockdown Techniques
Humans
Male
Molecular Sequence Data
Protein Conformation
Protein Transport genetics
Adaptor Protein Complex 1 genetics
Psoriasis genetics
Psoriasis metabolism
Toll-Like Receptor 3 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1537-6605
- Volume :
- 94
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- American journal of human genetics
- Publication Type :
- Academic Journal
- Accession number :
- 24791904
- Full Text :
- https://doi.org/10.1016/j.ajhg.2014.04.005