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Inhibition of CD82 improves colitis by increasing NLRP3 deubiquitination by BRCC3

Cellular & Molecular Immunology volume 20, pages 189–200 (2023)Cite this article

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Abstract

CD82 is a transmembrane protein that is involved in cancer suppression and activates immune cells; however, information on the NLRP3 inflammasome is limited. Herein, we show that although CD82 suppressed the activation of the NLRP3 inflammasome in vivo and in vitro, CD82 deficiency decreased the severity of colitis in mice. Furthermore, two binding partners of CD82, NLRP3 and BRCC3, were identified. CD82 binding to these partners increased the degradation of NLRP3 by blocking BRCC3-dependent K63-specific deubiquitination. Previous studies have shown that CD82-specific bacteria in the colon microbiota called Bacteroides vulgatus (B. vulgatus) regulated the expression of CD82 and promoted the activation of the NLRP3 inflammasome. Accordingly, we observed that B. vulgatus administration increased mouse survival by mediating CD82 expression and activating NLRP3 in mice with colitis. Overall, this study showed that CD82 suppression reduced the pathogenesis of colitis by elevating the activation of the NLRP3 inflammasome through BRCC3-dependent K63 deubiquitination. Based on our findings, we propose that B. vulgatus is a novel therapeutic candidate for colitis.

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Fig. 1: Inflammasome in macrophages
Fig. 2: CD82 deficiency led to activated NLRP3-dependent responses in vivo
Fig. 3: CD82 directly binds with NLRP3 or BRCC3
Fig. 4: TAT-CD82 (aa 152-158) is an essential region for binding to NLRP3 and BRCC3
Fig. 5: CD82 regulates the expression of NLRP3 by interacting with BRCC3.
Fig. 6: CD82-BRCC3 binding enhances NLRP3 ubiquitination.
Fig. 7: B. vulgatus specifically suppresses the expression and interaction of CD82 with BRCC3 in macrophages
Fig. 8: B. vulgatus exerts a therapeutic effect against acute DSS-induced colitis in mice

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This study includes no data deposited in external repositories.

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Acknowledgements

This work was supported by the NRF grant funded by the Korean government (MSIP) (2021R1A4A5032463) and the research fund of Hanyang University (HY-2021). We thank all members of the Infection Biology Laboratory for critical reading and discussion of the manuscript.

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Authors and Affiliations

  1. Department of Bionano Technology, Hanyang University, Seoul, 04673, Korea

    Jae-Sung Kim, Euni Cho & Seok-Jun Mun

  2. Institute of Natural Science & Technology, Hanyang University, Ansan, 15588, Korea

    Jae-Sung Kim

  3. Department of Molecular and Life Science, Hanyang University, Ansan, 15588, Korea

    Hyo Keun Kim, Sein Jang & Chul-Su Yang

  4. Center for Bionano Intelligence Education and Research, Ansan, 15588, Korea

    Hyo Keun Kim, Sein Jang, Euni Cho, Seok-Jun Mun & Chul-Su Yang

  5. Department of Computer Science, College of SW Convergence, Dankook University, Yongin, 16890, Korea

    Joongho Lee

  6. Department of Electronics & Electrical Engineering, College of Engineering, Dankook University, Yongin, 16890, Korea

    Seokhyun Yoon

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JSK, HKK, SJ, EC, and SJM performed molecular and animal experiments and analyzed the data. JL and SY analyzed the pyrosequencing data. CSY designed and conceptualized the research, supervised the experimental work, analyzed the data, and wrote the manuscript.

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Correspondence to Chul-Su Yang.

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Kim, JS., Kim, H.K., Lee, J. et al. Inhibition of CD82 improves colitis by increasing NLRP3 deubiquitination by BRCC3. Cell Mol Immunol 20, 189–200 (2023). https://doi.org/10.1038/s41423-022-00971-1

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