Identification of FAM173B as a protein methyltransferase promoting chronic pain

PLoS Biol. 2018 Feb 14;16(2):e2003452. doi: 10.1371/journal.pbio.2003452. eCollection 2018 Feb.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chromosomes, Human, Pair 5
  • Chronic Pain / enzymology*
  • Chronic Pain / genetics
  • Female
  • Gene Knockdown Techniques
  • Genome-Wide Association Study
  • HEK293 Cells
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism*
  • Humans
  • Male
  • Mice, Inbred C57BL
  • Microglia / metabolism
  • Polymorphism, Single Nucleotide
  • Reactive Oxygen Species / metabolism

Substances

  • Reactive Oxygen Species
  • ATPSCKMT protein, human
  • Atpsckmt protein, mouse
  • Histone-Lysine N-Methyltransferase

Grant support

EMBO http://www.embo.org/funding-awards/fellowships/short-term-fellowships (No grant number available) received by HW. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Boehringer Ingelheim Travel Grant https://www.bifonds.de/fellowships-grants/travel-grants.html (No grant number available) received by HW. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Utrecht University Life Science Seed Grant https://www.uu.nl/en/research/life-sciences/research/seed-grants (No grant number available) received by NE. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.