TY - JOUR
T1 - Tankyrase represses autoinflammation through the attenuation of TLR2 signaling
AU - Matsumoto, Yoshinori
AU - Dimitriou, Ioannis D.
AU - La Rose, Jose
AU - Lim, Melissa
AU - Camilleri, Susan
AU - Law, Napoleon
AU - Adissu, Hibret A.
AU - Tong, Jiefei
AU - Moran, Michael F.
AU - Chruscinski, Andrzej
AU - He, Fang
AU - Asano, Yosuke
AU - Katsuyama, Takayuki
AU - Sada, Kenei
AU - Wada, Jun
AU - Rottapel, Robert
N1 - Funding Information:
This work was supported by grants from the Canadian Institutes of Health Research, the Japan Society for the Promotion of Science, the Toray Science Foundation, the Japan Rheumatism Foundation, the Japan Foundation for Applied Enzymology, the Mochida Memorial Foundation, the Waksman Foundation of Japan Inc., the Japan Intractable Diseases Research Foundation, the Ichiro Kanehara Foundation for the Promotion of Medical Sciences and Medical Care, the Kanae Foundation for the Promotion of Medical Science, the Daiichi Sankyo Foundation of Life Science, the Astellas Foundation for Research on Metabolic Disorders, and the Senshin Medical Research Foundation. RR is supported by the Princess Margaret Cancer Centre and the Ontario Institute for Cancer Research.
Publisher Copyright:
Copyright: © 2022, Matsumoto et al.
PY - 2022/4/1
Y1 - 2022/4/1
N2 - Dysregulation of Toll-like receptor (TLR) signaling contributes to the pathogenesis of autoimmune diseases. Here, we provide genetic evidence that tankyrase, a member of the poly(ADP-ribose) polymerase (PARP) family, negatively regulates TLR2 signaling. We show that mice lacking tankyrase in myeloid cells developed severe systemic inflammation with high serum inflammatory cytokine levels. We provide mechanistic evidence that tankyrase deficiency resulted in tyrosine phosphorylation and activation of TLR2 and show that phosphorylation of tyrosine 647 within the TIR domain by SRC and SYK kinases was critical for TLR2 stabilization and signaling. Last, we show that the elevated cytokine production and inflammation observed in mice lacking tankyrase in myeloid cells were dependent on the adaptor protein 3BP2, which is required for SRC and SYK activation. These data demonstrate that tankyrase provides a checkpoint on the TLR-mediated innate immune response.
AB - Dysregulation of Toll-like receptor (TLR) signaling contributes to the pathogenesis of autoimmune diseases. Here, we provide genetic evidence that tankyrase, a member of the poly(ADP-ribose) polymerase (PARP) family, negatively regulates TLR2 signaling. We show that mice lacking tankyrase in myeloid cells developed severe systemic inflammation with high serum inflammatory cytokine levels. We provide mechanistic evidence that tankyrase deficiency resulted in tyrosine phosphorylation and activation of TLR2 and show that phosphorylation of tyrosine 647 within the TIR domain by SRC and SYK kinases was critical for TLR2 stabilization and signaling. Last, we show that the elevated cytokine production and inflammation observed in mice lacking tankyrase in myeloid cells were dependent on the adaptor protein 3BP2, which is required for SRC and SYK activation. These data demonstrate that tankyrase provides a checkpoint on the TLR-mediated innate immune response.
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U2 - 10.1172/JCI140869
DO - 10.1172/JCI140869
M3 - Article
C2 - 35362478
AN - SCOPUS:85127409146
SN - 0021-9738
VL - 132
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 7
M1 - e140869
ER -