Abstract
ABIN-1 (encoded by the gene Tnip1) is a ubiquitin-binding protein that can interact with ubiquitin-editing enzyme A20 (encoded by the gene TNFAIP3) to restrain the activation of necroptosis and NF-κB activation. Genetic variants in the genes Tnip1 and TNFAIP3 are both strongly associated with susceptibility to autoimmune chronic inflammatory diseases such as psoriasis vulgaris and systemic lupus erythematosus (SLE) in humans. Here we investigated the mechanism by which ABIN-1 regulated innate immune responses. We show that ABIN-1 heterozygosity sensitizes cells to antiviral response by mediating NF-κB-dependent and RIPK1-independent expression of pattern recognition molecules, including TLR3, RIG-I, and MDA5, in MEFs. Furthermore, we demonstrate that increased interaction of ABIN-1 and A20 with prolonged poly(I:C) stimulation of WT cells leads to A20-dependent reduction of ABIN-1 protein. Finally, we show that ABIN-1 heterozygosity sensitizes innate immune response of Abin-1+/− mice in vivo by promoting the production of proinflammatory cytokines, which can be blocked upon inhibition of RIPK1 kinase. Inhibition of RIPK1 kinase activity in vivo partially reduces the expression of MDA5, RIG-I, and caspase-11 in Abin-1+/− mice but not in WT mice. Thus, we conclude that ABIN-1 is a suppressor of innate immune response and the interaction of ABIN-1 with A20 controls innate immunity response through the NF-κB pathway and in both RIPK1 kinase activity-independent and dependent manner.
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Acknowledgements
This work was supported in part by grants from the NIA (1R01AG047231 and RF1AG055521) (to JY) and R01 AI 106934 (to DMK) and the China National Natural Science Foundation (31670798) (to ZS). We thank Dr. Averil Ma of UCSF for providing Abin-1−/− mice and A20−/− MEFs, Dr. Vishva Dixit of Genentech for Ripk3−/− mice and for ab against K48 ubiquitin chains, Dr. Manolis Pasparakis of U. Cologne, Germany and Dr. Michelle A. Kelliher of U. Mass for providing Ripk1D138N mice. We thank Dr. Roderick Bronson for mouse histopathology analysis. We thank the members of Yuan laboratory for stimulating discussions.
Author contributions
JY conceived the concept, designed the experiments, and wrote the manuscript. ZS designed the experiments, executed majority of the experiments, prepared the figures, and drafted manuscript. SAD, DH, VJB, NB, WL, LQ, NJ, DO, AN, and DMK conducted or designed specific experiments. HZ did genotyping.
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JY is a consultant of Denali Therapeutics. The other authors declare that they have no conflict of interest.
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Su, Z., Dziedzic, S.A., Hu, D. et al. ABIN-1 heterozygosity sensitizes to innate immune response in both RIPK1-dependent and RIPK1-independent manner. Cell Death Differ 26, 1077–1088 (2019). https://doi.org/10.1038/s41418-018-0215-3
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DOI: https://doi.org/10.1038/s41418-018-0215-3
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