Abstract
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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 digital issues and online access to articles
$119.00 per year
only $9.92 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Broz P, Dixit VM. Inflammasomes: mechanism of assembly, regulation and signalling. Nat Rev Immunol. 2016;16:407–20.
Swanson KV, Deng M, Ting JP. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat Rev Immunol. 2019;19:477–89.
Schroder K, Tschopp J. The inflammasomes. Cell. 2010;140:821–32.
Guo H, Callaway JB, Ting JP. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med. 2015;21:677–87.
Milner MT, Maddugoda M, Gotz J, Burgener SS, Schroder K. The NLRP3 inflammasome triggers sterile neuroinflammation and Alzheimer’s disease. Curr Opin Immunol. 2021;68:116–24.
Davis BK, Wen H, Ting JP. The inflammasome NLRs in immunity, inflammation, and associated diseases. Annu Rev Immunol. 2011;29:707–35.
Ge Q, Chen X, Zhao Y, Mu H, Zhang J. Modulatory mechanisms of NLRP3: Potential roles in inflammasome activation. Life Sci. 2021;267:118918.
Lopez-Castejon G. Control of the inflammasome by the ubiquitin system. Febs j. 2020;287:11–26.
Shim DW, Lee KH. Posttranslational Regulation of the NLR Family Pyrin Domain-Containing 3 Inflammasome. Front Immunol. 2018;9:1054.
Popovic D, Vucic D, Dikic I. Ubiquitination in disease pathogenesis and treatment. Nat Med. 2014;20:1242–53.
Humphries F, Bergin R, Jackson R, Delagic N, Wang B, Yang S, et al. The E3 ubiquitin ligase Pellino2 mediates priming of the NLRP3 inflammasome. Nat Commun. 2018;9:1560.
Song H, Liu B, Huai W, Yu Z, Wang W, Zhao J, et al. The E3 ubiquitin ligase TRIM31 attenuates NLRP3 inflammasome activation by promoting proteasomal degradation of NLRP3. Nat Commun. 2016;7:13727.
Py BF, Kim MS, Vakifahmetoglu-Norberg H, Yuan J. Deubiquitination of NLRP3 by BRCC3 critically regulates inflammasome activity. Mol Cell. 2013;49:331–8.
Palazon-Riquelme P, Worboys JD, Green J, Valera A, Martin-Sanchez F, Pellegrini C, et al. USP7 and USP47 deubiquitinases regulate NLRP3 inflammasome activation. EMBO Rep. 2018;19:e44766.
Hoss F, Rodriguez-Alcazar JF, Latz E. Assembly and regulation of ASC specks. Cell Mol Life Sci. 2017;74:1211–29.
Dick MS, Sborgi L, Ruhl S, Hiller S, Broz P. ASC filament formation serves as a signal amplification mechanism for inflammasomes. Nat Commun. 2016;7:11929.
Rodgers MA, Bowman JW, Fujita H, Orazio N, Shi M, Liang Q, et al. The linear ubiquitin assembly complex (LUBAC) is essential for NLRP3 inflammasome activation. J Exp Med. 2014;211:1333–47.
Shi CS, Shenderov K, Huang NN, Kabat J, Abu-Asab M, Fitzgerald KA, et al. Activation of autophagy by inflammatory signals limits IL-1beta production by targeting ubiquitinated inflammasomes for destruction. Nat Immunol. 2012;13:255–63.
Guan K, Wei C, Zheng Z, Song T, Wu F, Zhang Y, et al. MAVS Promotes Inflammasome Activation by Targeting ASC for K63-Linked Ubiquitination via the E3 Ligase TRAF3. J Immunol. 2015;194:4880–90.
Siu KL, Yuen KS, Castaño-Rodriguez C, Ye ZW, Yeung ML, Fung SY, et al. Severe acute respiratory syndrome coronavirus ORF3a protein activates the NLRP3 inflammasome by promoting TRAF3-dependent ubiquitination of ASC. Faseb j. 2019;33:8865–77.
Zhang L, Ko CJ, Li Y, Jie Z, Zhu L, Zhou X, et al. Peli1 facilitates NLRP3 inflammasome activation by mediating ASC ubiquitination. Cell Rep. 2021;37:109904.
Lee JY, Seo D, You J, Chung S, Park JS, Lee JH, et al. The deubiquitinating enzyme, ubiquitin-specific peptidase 50, regulates inflammasome activation by targeting the ASC adaptor protein. FEBS Lett. 2017;591:479–90.
Cheng YC, Shieh SY. Deubiquitinating enzyme USP3 controls CHK1 chromatin association and activation. Proc Natl Acad Sci USA. 2018;115:5546–51.
Grice GL, Nathan JA. The recognition of ubiquitinated proteins by the proteasome. Cell Mol Life Sci. 2016;73:3497–506.
Cai X, Xu H, Chen ZJ. Prion-Like Polymerization in Immunity and Inflammation. Cold Spring Harb Perspect Biol. 2017;9:a023580.
Pelegrin P, Barroso-Gutierrez C, Surprenant A. P2X7 receptor differentially couples to distinct release pathways for IL-1beta in mouse macrophage. J Immunol. 2008;180:7147–57.
Eisenbarth SC, Colegio OR, O’Connor W, Sutterwala FS, Flavell RA. Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature. 2008;453:1122–6.
Sokolovska A, Hem SL, HogenEsch H. Activation of dendritic cells and induction of CD4(+) T cell differentiation by aluminum-containing adjuvants. Vaccine. 2007;25:4575–85.
Guarda G, Braun M, Staehli F, Tardivel A, Mattmann C, Forster I, et al. Type I interferon inhibits interleukin-1 production and inflammasome activation. Immunity. 2011;34:213–23.
Guo Y, Li L, Xu T, Guo X, Wang C, Li Y, et al. HUWE1 mediates inflammasome activation and promotes host defense against bacterial infection. J Clin Investig. 2020;130:6301–16.
Xue Y, Enosi Tuipulotu D, Tan WH, Kay C, Man SM. Emerging Activators and Regulators of Inflammasomes and Pyroptosis. Trends Immunol. 2019;40:1035–52.
Cui J, Song Y, Li Y, Zhu Q, Tan P, Qin Y, et al. USP3 inhibits type I interferon signaling by deubiquitinating RIG-I-like receptors. Cell Res. 2014;24:400–16.
Fu S, Shao S, Wang L, Liu H, Hou H, Wang Y, et al. USP3 stabilizes p53 protein through its deubiquitinase activity. Biochem Biophys Res Commun. 2017;492:178–83.
Nicassio F, Corrado N, Vissers JH, Areces LB, Bergink S, Marteijn JA, et al. Human USP3 is a chromatin modifier required for S phase progression and genome stability. Curr Biol. 2007;17:1972–7.
Shi K, Zhang JZ, Yang L, Li NN, Yue Y, Du XH, et al. Protein deubiquitylase USP3 stabilizes Aurora A to promote proliferation and metastasis of esophageal squamous cell carcinoma. BMC Cancer. 2021;21:1196.
Liu B, Zhang M, Chu H, Zhang H, Wu H, Song G, et al. The ubiquitin E3 ligase TRIM31 promotes aggregation and activation of the signaling adaptor MAVS through Lys63-linked polyubiquitination. Nat Immunol. 2017;18:214–24.
Acknowledgements
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.
Author information
Authors and Affiliations
Contributions
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.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Supplementary information
Rights and permissions
Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
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). https://doi.org/10.1038/s41423-022-00917-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41423-022-00917-7