A NIK-SIX signaling axis controls inflammation by targeted silencing of noncanonical NF-κB

The non-canonical NF-κB signaling cascade is essential for lymphoid organogenesis, B-cell maturation, osteoclast differentiation, and inflammation in mammals 1 , 2 , whereas dysfunction of this system is associated with human diseases, including immunological disorders and cancer 3 – 6 . While contr...

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Bibliographic Details
Published in:Nature (London) 2019-03, Vol.568 (7751), p.249-253
Main Authors: Liu, Zixu, Mar, Katrina B., Hanners, Natasha W., Perelman, Sofya S., Kanchwala, Mohammed, Xing, Chao, Schoggins, John W., Alto, Neal M.
Format: Article
Language:English
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Summary:The non-canonical NF-κB signaling cascade is essential for lymphoid organogenesis, B-cell maturation, osteoclast differentiation, and inflammation in mammals 1 , 2 , whereas dysfunction of this system is associated with human diseases, including immunological disorders and cancer 3 – 6 . While controlled expression of NF-κB Inducing Kinase (NIK) is the rate-limiting step in non-canonical NF-κB activation 2 , 7 , mechanisms of inhibition remain largely unknown. Here, we report the identification of the sine oculis homeobox homolog family transcription factors SIX1 and SIX2 as essential inhibitory components of the non-canonical NF-κB signaling pathway. The developmentally silenced SIX -proteins are reactivated in differentiated macrophages by NIK-mediated suppression of the ubiquitin proteasome pathway. Consequently, SIX1 and SIX2 target a subset of inflammatory gene promoters and directly inhibit RelA and RelB trans -activation function in a negative feedback circuit. In support of a physiologically pivotal role for SIX -proteins in host immunity, human SIX1 transgene suppressed inflammation and promoted the recovery of mice from endotoxic shock. In addition, SIX1 and SIX2 protected RAS/p53-driven lung adenocarcinoma cells from inflammatory cell death induced by SMAC-mimetic chemotherapeutic agents, small-molecule activators of the non-canonical NF-κB pathway. Collectively, our study reveals a NIK- SIX signaling axis that fine-tunes inflammatory gene expression programs under both physiological and pathological conditions.
ISSN:0028-0836
1476-4687
DOI:10.1038/s41586-019-1041-6