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 9

Endogenous 3BP2 levels in macrophages controlled by tankyrase regulate the innate immune system.

Options: View larger image (or click on image) Download as PowerPoint
Endogenous 3BP2 levels in macrophages controlled by tankyrase regulate t...
(A) H&E staining of spleen, lymph node, colon, lung, and liver from 12-week-old Tnks+/+ Tnks2fl/fl (WT), Tnks–/– Tnks2fl/fl LysM-Cre (KO), and Tnks–/– Tnks2fl/fl Sh3bp2fl/fl LysM-Cre (TKO) mice. Scale bars: 250 μm (spleen, lung, and liver), 500 μm (lymph node and colon). (B) Serum levels of TNF-α, IL-6, IL-10, IL-17, and CCL3 in 12-week-old Tnks+/+ Tnks2fl/fl (WT), Tnks–/– Tnks2fl/fl LysM-Cre (KO), and Tnks–/– Tnks2fl/fl Sh3bp2fl/fl LysM-Cre (TKO) mice. ND, not detected. Three dots, 2 dots, and 2 dots are overlapped in the panels of TNF-α, IL-6, and IL-17, respectively. (C) qPCR analysis of Tnfa and Il6 mRNA expression in primary murine macrophages derived from Tnks+/+ Tnks2fl/fl (WT), Tnks–/– Tnks2fl/fl LysM-Cre (KO), and Tnks–/– Tnks2fl/fl Sh3bp2fl/fl LysM-Cre (TKO) mice; n = 3. (D) Whole-cell lysates from primary murine macrophages derived from Tnks+/+ Tnks2fl/fl (WT), Tnks–/– Tnks2fl/fl LysM-Cre (KO), and Tnks–/– Tnks2fl/fl Sh3bp2fl/fl LysM-Cre (TKO) mice, starved for 12 hours with 0.1% FBS and cultured in the presence of HKPG (107 cells/mL) for 0–120 minutes, were probed with the indicated antibodies for Western blot analysis. (E) Schematic model showing that tankyrase controls innate immunity, cytokine production, and inflammation through degradation of 3BP2, which accelerates SRC- and SYK-mediated TLR2 phosphorylation and activation. The images of TLR2 were adapted with permission from PDB-101, David S. Goodsell and the Research Collaboratory for Structural Bioinformatics (RCSB), Protein Data Bank (PDB) (62). P values were determined by ANOVA with Tukey-Kramer post hoc test. Data are presented as mean ± SEM. *P < 0.05.