Unknown

Dataset Information

0

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 ?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.

SUBMITTER: Setta-Kaffetzi N 

PROVIDER: S-EPMC4067562 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

altmetric image

Publications


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,  ...[more]

Similar Datasets

| S-EPMC8027616 | biostudies-literature
| S-EPMC8801405 | biostudies-literature
2023-06-04 | E-MTAB-11144 | biostudies-arrayexpress
| S-EPMC3169817 | biostudies-literature
| S-EPMC8698272 | biostudies-literature
| S-EPMC7477008 | biostudies-literature
2022-05-25 | GSE203415 | GEO
| S-EPMC6403101 | biostudies-literature
| S-EPMC10789831 | biostudies-literature
| S-EPMC10970016 | biostudies-literature