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TRIM21 regulates pyroptotic cell death by promoting Gasdermin D oligomerization

Abstract

Gasdermin-D (GSDMD), the executioner of pyroptotic cell death when it is cleaved by inflammatory caspases, plays a crucial role in host defense and the response to danger signals. So far, there are no known mechanisms, other than cleavage, for regulating GSDMD. Here, we show that tripartite motif protein TRIM21 acts as a positive regulator of GSDMD-dependent pyroptosis. TRIM21 interacted with GSDMD via its PRY-SPRY domain, maintaining GSDMD stable expression in resting cells yet inducing the N-terminus of GSDMD (GSDMD-N) aggregation during pyroptosis. TRIM21-deficient cells displayed a reduced cell death in response to NLRP3 or NLRC4 inflammasome activation. Genetic ablation of TRIM21 in mice conferred protection from LPS-induced inflammation and dextran sulfate sodium-induced colitis. Therefore, TRIM21 plays an essential role in GSDMD-mediated pyroptosis and may be a viable target for controlling and treating inflammation-associated diseases.

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Fig. 1: GSDMD directly interacts with TRIM21.
Fig. 2: TRIM21 binds GSDMD via its PRY-SPRY domain.
Fig. 3: TRIM21 enhances the stability of GSDMD independent of its E3 ligase activity.
Fig. 4: Depletion of TRIM21 alleviates pyroptosis.
Fig. 5: Depletion of TRIM21 reduces GSDMD-N upon inflammatory stimulation.
Fig. 6: The PRY-SPRY domain of TRIM21 promotes GSDMD-N oligomerization and cell death.
Fig. 7: TRIM21 deficiency ameliorates LPS-induced inflammation and DSS-induced colitis.

Data availability

All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the corresponding author.

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Acknowledgements

We thank Dr. H. Saiyin for the help in mouse tissue IHC experiments. Gsdmd/ HeLa cells and Gsdmd/ iBMDMs are kindly provided by Dr. F. Shao (National Institute of Biological Sciences, China). Gsdmd/ mice are kindly provided by Dr. Z. Lin (Nanjing University, China). WT pathogenic Salmonella typhimurium (SL14028s) is kindly provided by Dr. Y. Yao (Shanghai Jiaotong University, China).

Funding

This work was supported by grants from the National Natural Science Foundation of China (82071782, 31670878), the National Key Research and Development Project of China (2016YFA0500600), and the Shanghai Committee of Science and Technology (20XD1400800).

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JL, XC, and WG conceived and designed the study. WG, YL, XL, SW, PM, ZC, KL, SL, XX, JG, JW, CJ, CD, XL, YL, HH, JL, and HW performed the experiments and analyzed the data. JL and WG analyzed the data and wrote the paper. All authors discussed the results and commented on the paper.

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Correspondence to Xiangjun Chen or Jixi Li.

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All animal experiments were performed in accordance with the NIH Guide for the Care and Use of Laboratory Animals, with the approval of the Scientific Investigation Board of School of Life Sciences, Fudan University (2019-JS-011).

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Gao, W., Li, Y., Liu, X. et al. TRIM21 regulates pyroptotic cell death by promoting Gasdermin D oligomerization. Cell Death Differ (2021). https://doi.org/10.1038/s41418-021-00867-z

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