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

  • Cell Death Differ. 2026 Jan 8. doi: 10.1038/s41418-025-01654-w.
Chenglong Zhu  #  1  2  3 ,  Wangzheqi Zhang  #  2  3 ,  Yan Liao  #  2  3 ,  Ruoyu Jiang  3  4 ,  Lindong Cheng  2  3 ,  Yi Wang  1  2  3 ,  Tian Zhou  2  3 ,  Yijie Tao  5  6  7 ,  Sheng Xu  8 ,  Yizhi Yu  9 ,  Zui Zou  10  11  12
Affiliations
  • 1. National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, China.
  • 2. Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, China.
  • 3. School of Anesthesiology, Naval Medical University, Shanghai, China.
  • 4. Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Naval Medical University, Shanghai, China.
  • 5. National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, China. [email protected].
  • 6. Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, China. [email protected].
  • 7. School of Anesthesiology, Naval Medical University, Shanghai, China. [email protected].
  • 8. National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, China. [email protected].
  • 9. National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, China. [email protected].
  • 10. National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, China. [email protected].
  • 11. Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, China. [email protected].
  • 12. School of Anesthesiology, Naval Medical University, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 41507358 DOI: 10.1038/s41418-025-01654-w
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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