2022年2月
TANK prevents IFN-dependent fatal diffuse alveolar hemorrhage by suppressing DNA-cGAS aggregation.
Life science alliance
- ,
- ,
- 巻
- 5
- 号
- 2
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.26508/lsa.202101067
Diffuse alveolar hemorrhage (DAH) is one of the serious complications associated with systemic lupus erythematosus, an autoimmune disease whose pathogenesis involves type I IFNs and cytokines. Here, we show that TANK, a negative regulator of the NF-κB signaling via suppression of TRAF6 ubiquitination, is critical for the amelioration of fatal DAH caused by lung vascular endothelial cell death in a mouse model of systemic lupus erythematosus. The development of fatal DAH in the absence of TANK is mediated by type I IFN signaling, but not IL-6. We further uncover that STING, an adaptor essential for the signaling of cytoplasmic DNA sensor cyclic GMP-AMP (cGAMP) synthase (cGAS), plays a critical role in DAH under Tank deficiency. TANK controls cGAS-mediated cGAMP production and suppresses DNA-mediated induction of IFN-stimulated genes in macrophages by inhibiting the formation of DNA-cGAS aggregates containing ubiquitin. Collectively, TANK inhibits the cGAS-dependent recognition of cytoplasmic DNA to prevent fatal DAH in the murine lupus model.
- リンク情報
- ID情報
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- DOI : 10.26508/lsa.202101067
- PubMed ID : 34819357
- PubMed Central 記事ID : PMC8616552