APIP regulates the priming of canonical NLRP3 and non-canonical Caspase-11/4 inflammasomes by binding to TRAF6

  • Nat Commun. 2025 Dec 3;16(1):10866. doi: 10.1038/s41467-025-65893-8.
Kwangmin Jung  1 ,  Meiko Kawamura  2 ,  Bitna Lim  1 ,  Manabu Abe  2 ,  Kenji Sakimura  2 ,  Masaaki Komatsu  3 ,  Yong-Keun Jung  4
Affiliations
  • 1. School of Biological Sciences, Seoul National University, Seoul, Republic of Korea.
  • 2. Department of Animal Model Development, Brain Research Institute, Niigata University, Niigata, Japan.
  • 3. Department of Physiology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
  • 4. School of Biological Sciences, Seoul National University, Seoul, Republic of Korea. [email protected].
PMID: 41339302 DOI: 10.1038/s41467-025-65893-8
Abstract

Apaf-1-interacting protein (APIP) has been implicated in inflammation-related processes, including myocardial infarction and Cancer progression. However, its role in systemic inflammation remains elusive. Here, we investigate the APIP-mediated regulation of inflammasome activity in mice and human macrophages. Loss of APIP in the myeloid lineage (Apip cKO mice) compromises the activation of canonical NLRP3 and non-canonical caspase-11 inflammasomes, reducing Pyroptosis in bone marrow-derived macrophages (BMDM). Conversely, these inflammatory responses are enhanced in BMDMs from APIP-transgenic mice. Consistently, APIP knockdown in human macrophages inhibits the activation of NLRP3 and caspase-4 inflammasomes. Mechanistically, APIP binds to TRAF6, activating downstream NF-κB and JNK signaling and facilitating the priming of both inflammasomes. Importantly, systemic inflammation induced by LPS or Bacterial infection is attenuated in Apip cKO mice but exacerbated in APIP-transgenic mice. Thus, our findings suggest that APIP is crucial in regulating both canonical and non-canonical inflammasomes, presenting a potential therapeutic target for inflammatory diseases.

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