IL-1 induces mitochondrial translocation of IRAK2 to suppress oxidative metabolism in adipocytes

Nat Immunol. 2020 Oct;21(10):1219-1231. doi: 10.1038/s41590-020-0750-1. Epub 2020 Aug 10.

Abstract

Chronic inflammation is a common feature of obesity, with elevated cytokines such as interleukin-1 (IL-1) in the circulation and tissues. Here, we report an unconventional IL-1R-MyD88-IRAK2-PHB/OPA1 signaling axis that reprograms mitochondrial metabolism in adipocytes to exacerbate obesity. IL-1 induced recruitment of IRAK2 Myddosome to mitochondria outer membranes via recognition by TOM20, followed by TIMM50-guided translocation of IRAK2 into mitochondria inner membranes, to suppress oxidative phosphorylation and fatty acid oxidation, thereby attenuating energy expenditure. Adipocyte-specific MyD88 or IRAK2 deficiency reduced high-fat-diet-induced weight gain, increased energy expenditure and ameliorated insulin resistance, associated with a smaller adipocyte size and increased cristae formation. IRAK2 kinase inactivation also reduced high-fat diet-induced metabolic diseases. Mechanistically, IRAK2 suppressed respiratory super-complex formation via interaction with PHB1 and OPA1 upon stimulation of IL-1. Taken together, our results suggest that the IRAK2 Myddosome functions as a critical link between inflammation and metabolism, representing a novel therapeutic target for patients with obesity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / immunology*
  • Adipocytes / pathology
  • Animals
  • Cells, Cultured
  • Humans
  • Inflammation / immunology*
  • Interleukin-1 / metabolism*
  • Interleukin-1 Receptor-Associated Kinases / genetics
  • Interleukin-1 Receptor-Associated Kinases / metabolism*
  • Male
  • Mice
  • Mice, Knockout
  • Mitochondrial Membranes / metabolism*
  • Myeloid Differentiation Factor 88 / genetics
  • Myeloid Differentiation Factor 88 / metabolism
  • Obesity / immunology*
  • Oxidative Phosphorylation
  • Prohibitins
  • Protein Transport
  • Receptors, Interleukin-1 / metabolism
  • Signal Transduction

Substances

  • Interleukin-1
  • Myeloid Differentiation Factor 88
  • PHB protein, human
  • Prohibitins
  • Receptors, Interleukin-1
  • Interleukin-1 Receptor-Associated Kinases