ASC is essential for LPS-induced activation of procaspase-1 independently of TLR-associated signal adaptor molecules

Authors

  • Masatatsu Yamamoto,

    1. Department of Molecular Oncology Division of Molecular and Cellular Biology Institute on Ageing and Adaptation, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan
    2. Department of Cell Biology, Cancer Research Institute of the Japanese Foundation of Cancer Research, 1-37-1 Kamiikebukuro, Toshima-ku, Tokyo 170-8455, Japan
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  • Katsuyuki Yaginuma,

    1. Department of Cell Biology, Cancer Research Institute of the Japanese Foundation of Cancer Research, 1-37-1 Kamiikebukuro, Toshima-ku, Tokyo 170-8455, Japan
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  • Hiroko Tsutsui,

    1. Department of Immunology and Medical Zoology, Hyogo College of Medicine, 1-1 Mukogawa, Nishinomiya 663-8501, Japan
    2. Core Research of Evolutional Science and Technology, Japan Science and Technology agency, 4-1-8 Motomati, Kawaguchi 332-0012, Japan
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  • Junji Sagara,

    1. Department of Molecular Oncology Division of Molecular and Cellular Biology Institute on Ageing and Adaptation, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan
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  • Xin Guan,

    1. Department of Molecular Oncology Division of Molecular and Cellular Biology Institute on Ageing and Adaptation, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan
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  • Ekihiro Seki,

    1. Department of Immunology and Medical Zoology, Hyogo College of Medicine, 1-1 Mukogawa, Nishinomiya 663-8501, Japan
    2. Core Research of Evolutional Science and Technology, Japan Science and Technology agency, 4-1-8 Motomati, Kawaguchi 332-0012, Japan
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  • Koubun Yasuda,

    1. Department of Immunology and Medical Zoology, Hyogo College of Medicine, 1-1 Mukogawa, Nishinomiya 663-8501, Japan
    2. Core Research of Evolutional Science and Technology, Japan Science and Technology agency, 4-1-8 Motomati, Kawaguchi 332-0012, Japan
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  • Masahiro Yamamoto,

    1. Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, 3-1, Yamada-oka, Suita, Osaka 565-0871, Japan
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  • Shizuo Akira,

    1. Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, 3-1, Yamada-oka, Suita, Osaka 565-0871, Japan
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  • Kenji Nakanishi,

    1. Department of Immunology and Medical Zoology, Hyogo College of Medicine, 1-1 Mukogawa, Nishinomiya 663-8501, Japan
    2. Core Research of Evolutional Science and Technology, Japan Science and Technology agency, 4-1-8 Motomati, Kawaguchi 332-0012, Japan
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  • Tetsuo Noda,

    1. Department of Cell Biology, Cancer Research Institute of the Japanese Foundation of Cancer Research, 1-37-1 Kamiikebukuro, Toshima-ku, Tokyo 170-8455, Japan
    2. Department of Molecular Genetics, Tohoku University School of Medicine, 2-1 Seiryo-cho, Aoba-Ku, Sendai 980-8575, Japan
    3. Mouse Functional Genomics Research Group, Institute of Physical and Chemical Research (Japan) (RIKEN) Genomic Sciences Center, 214 Maeda-cho, Totsuka-ku, Yokohama, Kanagawa 244-0804, Japan
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  • Shun’ichiro Taniguchi

    Corresponding author
    1. Department of Molecular Oncology Division of Molecular and Cellular Biology Institute on Ageing and Adaptation, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan
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  • Communicated by: Shinichi Aizawa

* Correspondence: E-mail: stangch@sch.md.shinshu-u.ac.jp

Abstract

Toll-like receptors (TLRs) initiate a signalling cascade via association with an adaptor molecule, myeloid differentiation factor 88 (MyD88) and/or TIR domain-containing adaptor inducing-IFN-β (Trif), to induce various pro-inflammatory cytokines for microbial eradication. After stimulation of TLR4 with lipopolysaccharide (LPS), both IL-1β and IL-18 are processed, depending on the activation of caspase-1, although its mechanism remains unclear. ASC is an adapter protein possibly involved in the activation of procaspase-1. To unravel the requirement of ASC, we generated Asc−/– mice. Upon stimulation with LPS, Asc−/– macrophages failed in the processing of procaspase-1 and maturation of pro-IL-1β and pro-IL-18, but normally produced other pro-inflammatory cytokines including TNF-α and IL-6. MyD88−/– and Trif−/– macrophages showed normal activation of caspase-1, demonstrating a dispensable role for MyD88 and Trif. After, LPS-challenged Asc−/– mice lacked serum elevation of IL-1β and IL-18. Moreover, the Asc−/– mice exhibited neither acute liver injury nor lethal shock. These results demonstrate critical roles for ASC in the release of IL-1β/IL-18 via activation of caspase-1 and provide new insights into the inflammatory responses for host defence and diseases.

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