1. Academic Validation
  2. The APPL1-Rab5 axis restricts NLRP3 inflammasome activation through early endosomal-dependent mitophagy in macrophages

The APPL1-Rab5 axis restricts NLRP3 inflammasome activation through early endosomal-dependent mitophagy in macrophages

  • Nat Commun. 2021 Nov 17;12(1):6637. doi: 10.1038/s41467-021-26987-1.
Kelvin Ka Lok Wu 1 KeKao Long 1 Huige Lin 1 Parco Ming Fai Siu 2 Ruby Lai Chong Hoo 3 4 Dewei Ye 5 Aimin Xu 3 4 6 Kenneth King Yip Cheng 7
Affiliations

Affiliations

  • 1 Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China.
  • 2 School of Public Health, The University of Hong Kong, Pok Fu Lam, Hong Kong SAR, China.
  • 3 The State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Pok Fu Lam, Hong Kong SAR, China.
  • 4 Department of Pharmacology & Pharmacy, The University of Hong Kong, Pok Fu Lam, Hong Kong SAR, China.
  • 5 Guangdong Research Center of Metabolic Diseases of Integrated Western and Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China.
  • 6 Department of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong SAR, China.
  • 7 Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China. [email protected].
Abstract

Although Mitophagy is known to restrict NLRP3 inflammasome activation, the underlying regulatory mechanism remains poorly characterized. Here we describe a type of early endosome-dependent Mitophagy that limits NLRP3 inflammasome activation. Deletion of the endosomal adaptor protein APPL1 impairs Mitophagy, leading to accumulation of damaged mitochondria producing Reactive Oxygen Species (ROS) and oxidized cytosolic mitochondrial DNA, which in turn trigger NLRP3 inflammasome overactivation in macrophages. NLRP3 Agonist causes APPL1 to translocate from early endosomes to mitochondria, where it interacts with Rab5 to facilitate endosomal-mediated Mitophagy. Mice deficient for APPL1 specifically in hematopoietic cell are more sensitive to endotoxin-induced sepsis, obesity-induced inflammation and glucose dysregulation. These are associated with increased expression of systemic interleukin-1β, a major product of NLRP3 inflammasome activation. Our findings indicate that the early endosomal machinery is essential to repress NLRP3 inflammasome hyperactivation by promoting Mitophagy in macrophages.

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