Abstract
Type I interferon (IFN) production plays pivotal roles in host antiviral innate immune responses, but an excessive production of type I IFN leads to the development of immunopathological conditions. Investigations on the regulatory mechanisms underlying host type I IFN production are currently of great interest. Here, we found that the expression of lectin family member Siglec1 was upregulated by viral infection in macrophages, which was dependent on the IFN/JAK/STAT1 signaling pathway. Siglec1 was found to negatively regulate viral infection-triggered type I IFN production. Mechanistically, Siglec1 associates with DAP12 to recruit and activate the scaffolding function of SHP2; SHP2 then recruits E3 ubiquitin ligase TRIM27, which induces TBK1 degradation via K48-linked ubiquitination at Lys251 and Lys372. Therefore, viral infection-induced upregulation of Siglec1 feedback loop inhibits type I IFN production and suppresses antiviral innate immune responses. Our study outlines a novel mechanism of negative regulation of type I IFN production, which may help virus to escape immune elimination.
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Acknowledgements
We thank Ms Tingting Fang, Mei Jin, and Yan Li for technical assistance, Drs Chaofeng Han, Xingguang Liu, Sheng Xu, Yanmei Han, and Taoyong Chen for valuable discussions. This work was supported by the National Basic Research Program of China (2013CB530502 and 2012CB518900), and the National Natural Science Foundation of China (81123006, 31300718, 31370864, and 81422037).
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( Supplementary information is linked to the online version of the paper on the Cell Research website.)
Supplementary information
Supplementary information, Figure S1
Siglec1's promoter has ISRE binding site (Related to Figure 1). (PDF 100 kb)
Supplementary information, Figure S2
Siglec1 suppresses VSV-triggered type I IFN production in cDC (Related to Figure 2). (PDF 64 kb)
Supplementary information, Figure S3
Human Siglec1-mediated inhibition of type I IFN production is dependent on TBK1 and upstream of IRF3 (Related to Figure 3). (PDF 102 kb)
Supplementary information, Figure S4
Siglec1 associates with DAP12 and TRIM27 in cells upon viral infection (Related to Figure 4). (PDF 31 kb)
Supplementary information, Figure S5
Recruitment of TRIM27 by SHP2 inhibits VSV-triggered type I IFN production in macrophages (Related to Figure 5). (PDF 99 kb)
Supplementary information, Figure S6
TRIM27 directly binds SHP2 and TBK1, and TRIM27 mediates TBK1 degradation (Related to Figure 6). (PDF 295 kb)
Supplementary information, Figure S7
Mutant of TBK1(K372/251R) binds TRIM27 (Related to Figure 7). (PDF 34 kb)
Supplementary information, Table S1
siRNA sequences used for RNA interference (PDF 40 kb)
Supplementary information, Table S2
Primers used for Q-PCR (PDF 39 kb)
Supplementary information, Table S3
PCR primers used for gene cloning (PDF 44 kb)
Supplementary information, Table S4
PCR primers used for TBK1 mutants (PDF 39 kb)
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Zheng, Q., Hou, J., Zhou, Y. et al. Siglec1 suppresses antiviral innate immune response by inducing TBK1 degradation via the ubiquitin ligase TRIM27. Cell Res 25, 1121–1136 (2015). https://doi.org/10.1038/cr.2015.108
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DOI: https://doi.org/10.1038/cr.2015.108
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