Unknown

Dataset Information

0

Wiskott-Aldrich syndrome protein restricts cGAS/STING activation by dsDNA immune complexes.


ABSTRACT: Dysregulated sensing of self-nucleic acid is a leading cause of autoimmunity in multifactorial and monogenic diseases. Mutations in Wiskott-Aldrich syndrome protein (WASp), a key regulator of cytoskeletal dynamics in immune cells, cause autoimmune manifestations and increased production of type I IFNs by innate cells. Here we show that immune complexes of self-DNA and autoantibodies (DNA-ICs) contribute to elevated IFN levels via activation of the cGAS/STING pathway of cytosolic sensing. Mechanistically, lack of endosomal F-actin nucleation by WASp caused a delay in endolysosomal maturation and prolonged the transit time of ingested DNA-ICs. Stalling in maturation-defective organelles facilitated leakage of DNA-ICs into the cytosol, promoting activation of the TBK1/STING pathway. Genetic deletion of STING and STING and cGAS chemical inhibitors abolished IFN production and rescued systemic activation of IFN-stimulated genes in vivo. These data unveil the contribution of cytosolic self-nucleic acid sensing in WAS and underscore the importance of WASp-mediated endosomal actin remodeling in preventing innate activation.

SUBMITTER: Piperno GM 

PROVIDER: S-EPMC7526445 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

altmetric image

Publications


Dysregulated sensing of self-nucleic acid is a leading cause of autoimmunity in multifactorial and monogenic diseases. Mutations in Wiskott-Aldrich syndrome protein (WASp), a key regulator of cytoskeletal dynamics in immune cells, cause autoimmune manifestations and increased production of type I IFNs by innate cells. Here we show that immune complexes of self-DNA and autoantibodies (DNA-ICs) contribute to elevated IFN levels via activation of the cGAS/STING pathway of cytosolic sensing. Mechani  ...[more]

Similar Datasets

| S-EPMC3613928 | biostudies-literature
| S-EPMC8384432 | biostudies-literature
| S-EPMC5691069 | biostudies-literature
| S-EPMC3399097 | biostudies-literature
| S-EPMC3064520 | biostudies-literature
| S-EPMC2789278 | biostudies-literature
| S-EPMC3760724 | biostudies-literature
| S-EPMC3777703 | biostudies-literature
| S-EPMC1783416 | biostudies-literature
| S-EPMC8436742 | biostudies-literature