Spontaneous activation of a MAVS-dependent antiviral signaling pathway determines high basal interferon-β expression in cardiac myocytes

J Mol Cell Cardiol. 2017 Oct;111:102-113. doi: 10.1016/j.yjmcc.2017.08.008. Epub 2017 Aug 16.

Abstract

Viral myocarditis is a leading cause of sudden death in young adults as the limited turnover of cardiac myocytes renders the heart particularly vulnerable to viral damage. Viruses induce an antiviral type I interferon (IFN-α/β) response in essentially all cell types, providing an immediate innate protection. Cardiac myocytes express high basal levels of IFN-β to help pre-arm them against viral infections, however the mechanism underlying this expression remains unclear. Using primary cultures of murine cardiac and skeletal muscle cells, we demonstrate here that the mitochondrial antiviral signaling (MAVS) pathway is spontaneously activated in unstimulated cardiac myocytes but not cardiac fibroblasts or skeletal muscle cells. Results suggest that MAVS association with the mitochondrial-associated ER membranes (MAM) is a determinant of high basal IFN-β expression, and demonstrate that MAVS is essential for spontaneous high basal expression of IFN-β in cardiac myocytes and the heart. Together, results provide the first mechanism for spontaneous high expression of the antiviral cytokine IFN-β in a poorly replenished and essential cell type.

Keywords: Cardiac myocyte; Cardiomyocyte; Interferon; MAM; MAVS; Mitochondria.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Aging / metabolism
  • Animals
  • Antiviral Agents / metabolism*
  • Female
  • Fibroblasts / metabolism
  • Fibroblasts / virology
  • Interferon-Induced Helicase, IFIH1 / metabolism
  • Interferon-beta / metabolism*
  • Mammalian orthoreovirus 3 / physiology
  • Mice, Inbred C57BL
  • Mitochondria / metabolism
  • Mitochondrial Proteins / metabolism
  • Muscle Fibers, Skeletal / metabolism
  • Myocardium / metabolism
  • Myocytes, Cardiac / metabolism*
  • Myocytes, Cardiac / virology
  • Peroxisomes / metabolism
  • Protein-Serine-Threonine Kinases / metabolism
  • Repressor Proteins / metabolism
  • Signal Transduction*

Substances

  • Adaptor Proteins, Signal Transducing
  • Antiviral Agents
  • Atf7ip protein, mouse
  • IPS-1 protein, mouse
  • Mitochondrial Proteins
  • Repressor Proteins
  • Interferon-beta
  • Tbk1 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Ifih1 protein, mouse
  • Interferon-Induced Helicase, IFIH1