| First Author | Piperno GM | Year | 2020 |
| Journal | JCI Insight | Volume | 5 |
| Issue | 17 | PubMed ID | 32721945 |
| Mgi Jnum | J:339052 | Mgi Id | MGI:6753781 |
| Doi | 10.1172/jci.insight.132857 | Citation | Piperno GM, et al. (2020) Wiskott-Aldrich syndrome protein restricts cGAS/STING activation by dsDNA immune complexes. JCI Insight 5(17) |
| abstractText | 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. |
