TY - JOUR
T1 - TBK1 recruitment to STING mediates autoinflammatory arthritis caused by defective DNA clearance
AU - Li, Tong
AU - Yum, Seoyun
AU - Li, Minghao
AU - Chen, Xiang
AU - Zuo, Xiaoxia
AU - Chen, Zhijian J.
N1 - Funding Information:
This work was supported by grants from the Cancer Prevention and Research Institute of Texas (RP180725) and the Welch Foundation (I-1389). Z.J. Chen is an investigator of the Howard Hughes Medical Institute.
Publisher Copyright:
© 2021 Li et al.
PY - 2021/12/13
Y1 - 2021/12/13
N2 - Defective DNA clearance in DNase II-/- mice leads to lethal inflammatory diseases that can be rescued by deleting cGAS or STING, but the role of distinct signaling pathways downstream of STING in the disease manifestation is not known. We found that the STING S365A mutation, which abrogates IRF3 binding and type I interferon induction, rescued the embryonic lethality of DNase II-/- mice. However, the STING S365A mutant retains the ability to recruit TBK1 and activate NF-κB, and DNase II-/- STING-S365A mice exhibited severe polyarthritis, which was alleviated by neutralizing antibodies against TNF-α or IL-6 receptor. In contrast, the STING L373A mutation or C-terminal tail truncation, which disrupts TBK1 binding and therefore prevents activation of both IRF3 and NF-κB, completely rescued the phenotypes of DNase II-/- mice. These results demonstrate that TBK1 recruitment to STING mediates autoinflammatory arthritis independently of type I interferons. Inhibiting TBK1 binding to STING may be a therapeutic strategy for certain autoinflammatory diseases instigated by self-DNA.
AB - Defective DNA clearance in DNase II-/- mice leads to lethal inflammatory diseases that can be rescued by deleting cGAS or STING, but the role of distinct signaling pathways downstream of STING in the disease manifestation is not known. We found that the STING S365A mutation, which abrogates IRF3 binding and type I interferon induction, rescued the embryonic lethality of DNase II-/- mice. However, the STING S365A mutant retains the ability to recruit TBK1 and activate NF-κB, and DNase II-/- STING-S365A mice exhibited severe polyarthritis, which was alleviated by neutralizing antibodies against TNF-α or IL-6 receptor. In contrast, the STING L373A mutation or C-terminal tail truncation, which disrupts TBK1 binding and therefore prevents activation of both IRF3 and NF-κB, completely rescued the phenotypes of DNase II-/- mice. These results demonstrate that TBK1 recruitment to STING mediates autoinflammatory arthritis independently of type I interferons. Inhibiting TBK1 binding to STING may be a therapeutic strategy for certain autoinflammatory diseases instigated by self-DNA.
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U2 - 10.1084/jem.20211539
DO - 10.1084/jem.20211539
M3 - Article
C2 - 34901991
AN - SCOPUS:85122679451
SN - 0022-1007
VL - 219
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 1
M1 - e20211539
ER -