PT  - JOURNAL ARTICLE
AU  - Atsuko Wakabayashi
AU  - Masanori Yoshinaga
AU  - Osamu Takeuchi
TI  - TANK prevents IFN-dependent fatal diffuse alveolar hemorrhage by suppressing DNA-cGAS aggregation
AID  - 10.26508/lsa.202101067
DP  - 2022 Feb 01
TA  - Life Science Alliance
PG  - e202101067
VI  - 5
IP  - 2
4099  - https://www.life-science-alliance.org/content/5/2/e202101067.short
4100  - https://www.life-science-alliance.org/content/5/2/e202101067.full
SO  - Life Sci. Alliance2022 Feb 01; 5
AB  - 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.