Identification of FAM173B as a protein methyltransferase promoting chronic pain

  • PLoS Biol. 2018 Feb 14;16(2):e2003452. doi: 10.1371/journal.pbio.2003452.
Hanneke L D M Willemen  1 ,  Annemieke Kavelaars  2 ,  Judith Prado  3 ,  Mirjam Maas  1 ,  Sabine Versteeg  1 ,  Lara J J Nellissen  1 ,  Jeshua Tromp  1 ,  Rafael Gonzalez Cano  1  4 ,  Wenjun Zhou  2 ,  Magnus E Jakobsson  5 ,  Jędrzej Małecki  5 ,  George Posthuma  6 ,  Abdella M Habib  7  8 ,  Cobi J Heijnen  2 ,  Pål Ø Falnes  5 ,  Niels Eijkelkamp  1  3
Affiliations
  • 1. Laboratory of Neuroimmunology and Developmental Origins of Disease (NIDOD), University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
  • 2. Laboratory of Neuroimmunology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America.
  • 3. Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
  • 4. Department of Pharmacology and Institute of Neuroscience, University of Granada, Granada, Spain.
  • 5. Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway.
  • 6. Department of Cell Biology and Institute of Biomembranes, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
  • 7. Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London, United Kingdom.
  • 8. College of Medicine, Member of Qatar Health, Qatar University, Doha, Qatar.
PMID: 29444090 DOI: 10.1371/journal.pbio.2003452
Abstract

Chronic Pain is a debilitating problem, and insights in the neurobiology of Chronic Pain are needed for the development of novel Pain therapies. A genome-wide association study implicated the 5p15.2 region in chronic widespread Pain. This region includes the coding region for FAM173B, a functionally uncharacterized protein. We demonstrate here that FAM173B is a mitochondrial lysine methyltransferase that promotes Chronic Pain. Knockdown and sensory neuron overexpression strategies showed that FAM173B is involved in persistent inflammatory and neuropathic Pain via a pathway dependent on its methyltransferase activity. FAM173B methyltransferase activity in sensory neurons hyperpolarized mitochondria and promoted macrophage/microglia activation through a reactive oxygen species-dependent pathway. In summary, we uncover a role for methyltransferase activity of FAM173B in the neurobiology of Pain. These results also highlight FAM173B methyltransferase activity as a potential therapeutic target to treat debilitating Chronic Pain conditions.