Celastrol suppresses humoral immune responses and autoimmunity by targeting the COMMD3/8 complex

doi:10.1126/sciimmunol.adc9324

. 2023 Mar 31;8(81):eadc9324.

doi: 10.1126/sciimmunol.adc9324. Epub 2023 Mar 31.

Celastrol suppresses humoral immune responses and autoimmunity by targeting the COMMD3/8 complex

Taiichiro Shirai^{1

2}, Akiko Nakai^{1

3}, Emiko Ando¹, Jun Fujimoto^{1

4}, Sarah Leach¹, Takao Arimori⁵, Daisuke Higo⁶, Floris J van Eerden^{7

8}, Janyerkye Tulyeu^{9

10}, Yu-Chen Liu¹¹, Daisuke Okuzaki^{10

11

12}, Masanori A Murayama¹³, Haruhiko Miyata¹⁴, Kazuto Nunomura¹⁵, Bangzhong Lin¹⁵, Akiyoshi Tani¹⁵, Atsushi Kumanogoh^{4

10

16

17}, Masahito Ikawa^{10

14}, James B Wing^{9

10}, Daron M Standley^{7

8

10}, Junichi Takagi^{5

17}, Kazuhiro Suzuki^{1

2

3

10}

Affiliations

¹ Laboratory of Immune Response Dynamics, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
² Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
³ Department of Immune Response Dynamics, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
⁴ Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
⁵ Laboratory for Protein Synthesis and Expression, Institute for Protein Research, Osaka University, Suita, Osaka, Japan.
⁶ Thermo Fisher Scientific K.K., Yokohama, Kanagawa, Japan.
⁷ Laboratory of Systems Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
⁸ Department of Genome Informatics, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
⁹ Laboratory of Human Single Cell Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
¹⁰ Center for Infectious Disease Education and Research, Osaka University, Suita, Osaka, Japan.
¹¹ Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
¹² Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
¹³ Department of Animal Models for Human Diseases, Institute of Biomedical Science, Kansai Medical University, Hirakata, Osaka, Japan.
¹⁴ Department of Experimental Genome Research, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
¹⁵ Center for Supporting Drug Discovery and Life Science Research, Graduate School of Pharmaceutical Science, Osaka University, Suita, Osaka, Japan.
¹⁶ Laboratory of Immunopathology, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
¹⁷ Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Osaka, Japan.

PMID: 37000855
DOI: 10.1126/sciimmunol.adc9324

Celastrol suppresses humoral immune responses and autoimmunity by targeting the COMMD3/8 complex

Taiichiro Shirai et al. Sci Immunol. 2023.

. 2023 Mar 31;8(81):eadc9324.

doi: 10.1126/sciimmunol.adc9324. Epub 2023 Mar 31.

Authors

Affiliations

¹ Laboratory of Immune Response Dynamics, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
² Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
³ Department of Immune Response Dynamics, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
⁴ Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
⁵ Laboratory for Protein Synthesis and Expression, Institute for Protein Research, Osaka University, Suita, Osaka, Japan.
⁶ Thermo Fisher Scientific K.K., Yokohama, Kanagawa, Japan.
⁷ Laboratory of Systems Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
⁸ Department of Genome Informatics, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
⁹ Laboratory of Human Single Cell Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
¹⁰ Center for Infectious Disease Education and Research, Osaka University, Suita, Osaka, Japan.
¹¹ Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
¹² Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
¹³ Department of Animal Models for Human Diseases, Institute of Biomedical Science, Kansai Medical University, Hirakata, Osaka, Japan.
¹⁴ Department of Experimental Genome Research, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
¹⁵ Center for Supporting Drug Discovery and Life Science Research, Graduate School of Pharmaceutical Science, Osaka University, Suita, Osaka, Japan.
¹⁶ Laboratory of Immunopathology, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
¹⁷ Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Osaka, Japan.

PMID: 37000855
DOI: 10.1126/sciimmunol.adc9324

Abstract

Celastrol, a bioactive molecule extracted from the Tripterygium wilfordii plant, has been shown to exhibit anti-inflammatory properties. However, its mechanism of action has not been fully elucidated. Here, we show that celastrol suppresses humoral immune responses and autoimmunity by disabling a protein complex consisting of copper metabolism MURR1 domain-containing (COMMD) 3 and COMMD8 (COMMD3/8 complex), a signaling adaptor for chemoattractant receptors. Having demonstrated the involvement of the COMMD3/8 complex in a mouse model of rheumatoid arthritis, we identified celastrol as a compound that covalently bound to and dissociated the COMMD3/8 complex. Celastrol inhibited B cell migration, reduced antibody responses, and blocked arthritis progression, recapitulating deficiency of the COMMD3/8 complex. These effects of celastrol were abolished in mice expressing a celastrol-resistant mutant of the COMMD3/8 complex. These findings establish that celastrol exerts immunosuppressive activity by targeting the COMMD3/8 complex. Our study suggests that the COMMD3/8 complex is a potentially druggable target in autoimmune diseases and points to celastrol as a lead pharmacologic candidate in this capacity.

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Celastrol suppresses humoral immune responses and autoimmunity by targeting the COMMD3/8 complex

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Celastrol suppresses humoral immune responses and autoimmunity by targeting the COMMD3/8 complex

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