Tankyrase represses autoinflammation through the attenuation of TLR2 signaling
Yoshinori Matsumoto, … , Jun Wada, Robert Rottapel
Yoshinori Matsumoto, … , Jun Wada, Robert Rottapel
Published April 1, 2022
Citation Information: J Clin Invest. 2022;132(7):e140869. https://doi.org/10.1172/JCI140869.
View: Text | PDF
Research Article Autoimmunity Inflammation

Tankyrase represses autoinflammation through the attenuation of TLR2 signaling

Abstract

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.

Authors

Yoshinori Matsumoto, Ioannis D. Dimitriou, Jose La Rose, Melissa Lim, Susan Camilleri, Napoleon Law, Hibret A. Adissu, Jiefei Tong, Michael F. Moran, Andrzej Chruscinski, Fang He, Yosuke Asano, Takayuki Katsuyama, Ken-ei Sada, Jun Wada, Robert Rottapel

×

Figure 2

TIR domain tyrosines are required for the stability of TLR2.

Options: View larger image (or click on image) Download as PowerPoint
TIR domain tyrosines are required for the stability of TLR2. (A) Whole-c...
(A) Whole-cell lysates from HEK293T cells cotransfected with the indicated constructs were probed with the indicated antibodies for Western blot analysis. (B) Nonradioactive pulse-chase assay to analyze turnover of TLR2 (WT) or TLR2 (6YF) protein labeled with Click-IT Metabolic Labeling. Biotinylated proteins were probed with the indicated antibodies, and the percentages of TLR2 protein levels were plotted as a function of time. (C, D, and F) HEK293T cells were cotransfected with the indicated constructs, and Myc-TLR2 (C and D) or GST-MyD88 (F) immune complexes and whole-cell lysates (WCL) were probed with the indicated antibodies for Western blot analysis. (E) Luciferase activity from an NF-κB reporter assay in HEK293T cells cotransfected with the indicated constructs; n = 3. P values were determined by unpaired t test (A, C, D, and F) or ANOVA with Tukey-Kramer post hoc test (E). Data are presented as mean ± SEM. *P < 0.05.