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USP3 deubiquitinates and stabilizes the adapter protein ASC to regulate inflammasome activation


Inflammasomes are essential components of the innate immune system and its defense against infections, whereas the dysregulation of inflammasome activation has a detrimental effect on human health. The activation of inflammasomes is subjected to tight regulation to maintain immune homeostasis, yet the underlying mechanism remains elusive. Here, we identify USP3 as a direct deubiquitinating enzyme (DUB) for ASC, the central adapter mediating the assembly and activation of most inflammasomes. USP3 removes the K48-linked ubiquitination on ASC and strengthens its stability by blocking proteasomal degradation. Additionally, USP3 promotes inflammasome activation, and this function was confirmed in mouse models of aluminum (Alum)-induced peritonitis, F. novicida infection and flagellin-induced pneumonia in vivo. Our work unveils that USP3 functions as a key regulator of ASC ubiquitination and maintains the physiological role of ASC in mediating inflammasome activation, and we propose a new mechanism by which the ubiquitination of ASC regulates inflammasome activation.

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This work was supported by grants from the National Key Research and Development Program (2021YFC2300603), the National Natural Science Foundation of China (32000633, 31730026, 81930039), the Natural Science Foundation of Shandong Province (ZR2020QH136), the China Postdoctoral Science Foundation (2020M682187), and the Postdoctoral Innovation Project of Shandong Province (202002012). We thank Dr. Xiaopeng Qi (Shandong University) for the F. novicida strain U112.

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Authors and Affiliations



CG conceived the research; CG and FL designed the experiments; WZ and FL performed the research; LZ, YZ, BL, CM, WZ, and SL, provided discussions; CG and FL analyzed the data; CG and FL wrote the paper.

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Correspondence to Feng Liu or Chengjiang Gao.

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The authors declare no competing interests.

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Zhuang, W., Zhang, L., Zheng, Y. et al. USP3 deubiquitinates and stabilizes the adapter protein ASC to regulate inflammasome activation. Cell Mol Immunol 19, 1141–1152 (2022).

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  • ASC
  • inflammasome
  • K48-linked ubiquitination
  • proteasomal degradation
  • USP3


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