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ERK/Smurf1 regulates non-canonical pyroptosis by prompting Caspase-11 ubiquitination

Cell Death & Differentiation (2026)Cite this article

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Abstract

Sepsis, a devastating microbe-induced inflammatory response, culminates in multi-organ dysfunction, with pyroptosis mediated by the non-canonical inflammasome being a pivotal factor. The mouse Caspase-11, central to this pathway, is directly activated by cytoplasmic lipopolysaccharide (LPS). Although ubiquitination is known to tightly regulate the inflammatory response in pyroptosis, its role in modulating the non-canonical inflammasome remains enigmatic. In this study, we unveil that the E3 ubiquitin ligase Smurf1 is a critical negative regulator of the non-canonical inflammasome pathway. Smurf1 orchestrates K48-linked polyubiquitination of Caspase-11 at K245 and K247 residues, leading to its degradation via the 26S proteasome. This process is further amplified by ERK phosphorylation of Smurf1 at the S148 site. In parallel, Caspase-11 modulates Smurf1 protein content through cleavage. Notably, macrophage-specific Smurf1 deficiency exacerbates sepsis-induced mortality in mice, attributed to the hyperactivation of the non-canonical inflammasome. Conversely, targeted supplementation of Smurf1 in macrophages mitigates the high mortality and inflammatory response associated with sepsis. Thus, Smurf1 emerges as a key player in modulating the activation of the non-canonical inflammasome in response to Gram-negative bacterial infections.

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Fig. 1: Smurf1 inhibits Caspase-11-induced non-canonical pyroptosis, which is dependent on its E3 ubiquitin ligase activity.
Fig. 2: Smurf1 interacts with endogenous and exogenous Caspase-11.
Fig. 3: Smurf1 mediates ubiquitination of k48-linked Caspase-11, and ubiquitinated Caspase-11 is degraded via the 26S proteasome.
Fig. 4: ERK binds to Smurf1 and phosphorylates Smurf1 at the S148 site.
Fig. 5: Phosphorylation of Smurf1 is critical for Caspase-11 ubiquitination.
Fig. 6: Caspase-11 cleaves Smurf1 to prevent its own ubiquitination degradation.
Fig. 7: Macrophage-specific deletion of Smurf1 exacerbates endotoxic shock.
Fig. 8: Targeting macrophages with overexpression of Smurf1 ameliorates endotoxic shock and CLP-induced sepsis.

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Data availability

Data supporting the present study are available from the corresponding author upon reasonable request.

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Funding

This work was supported by the National Natural Science Foundation of China (No. 32400760, 82572494), Shanghai Industrial Collaborative Innovation Project (No. HCXBCY-2023-041, HCXBCY-2024-033, XTCX-KJ-2024-39), Shanghai Oriental Talents Program (Outstanding Talents Project), 2024 Medical Technology Key Research Project of the Chinese Medical Education Association (No. 2024KTZ011), and 2024 Basic Medicine Innovation Open Project of Naval Medical University (supported by National Key Laboratory of Immunity and Inflammation, No. JCKFKT-MS-002), Naval Medical University Key Cultivation Program for Outstanding Doctoral Dissertations, and partner laboratory of basic medicine school of Naval Medical University (JCHZJL-009).

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  1. These authors contributed equally: Chenglong Zhu, Wangzheqi Zhang, Yan Liao.

Authors and Affiliations

  1. National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, China

    Chenglong Zhu, Yi Wang, Yijie Tao, Sheng Xu, Yizhi Yu & Zui Zou

  2. Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, China

    Chenglong Zhu, Wangzheqi Zhang, Yan Liao, Lindong Cheng, Yi Wang, Tian Zhou, Yijie Tao & Zui Zou

  3. School of Anesthesiology, Naval Medical University, Shanghai, China

    Chenglong Zhu, Wangzheqi Zhang, Yan Liao, Ruoyu Jiang, Lindong Cheng, Yi Wang, Tian Zhou, Yijie Tao & Zui Zou

  4. Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Naval Medical University, Shanghai, China

    Ruoyu Jiang

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Contributions

ZZ, YY, SX, and YT designed and supervised the research. CZ, WZ, YL, RJ, LC, YW, TZ, and YT performed research. CZ, WZ, and YL collected clinical samples and performed analyses. LC and RJ performed bioinformatics analyses. ZZ, YY, SX, and YT provided financial support. ZZ, YY, SX, and CZ analyzed data and wrote the paper. CZ, WZ, and YL contributed equally.

Corresponding authors

Correspondence to Yijie Tao, Sheng Xu, Yizhi Yu or Zui Zou.

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All animal experiments were approved by the Animal Care Committee of Naval Medical University. PBMC sample collection was approved by Biomedical Research Ethics Committee of Naval Medical University. The informed consent was obtained from all participants. This study was conducted in accordance with all relevant guidelines and regulations.

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Zhu, C., Zhang, W., Liao, Y. et al. ERK/Smurf1 regulates non-canonical pyroptosis by prompting Caspase-11 ubiquitination. Cell Death Differ (2026). https://doi.org/10.1038/s41418-025-01654-w

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