The kinase Jnk2 promotes stress-induced mitophagy by targeting the small mitochondrial form of the tumor suppressor ARF for degradation

Nat Immunol. 2015 May;16(5):458-66. doi: 10.1038/ni.3130. Epub 2015 Mar 23.


Mitophagy is essential for cellular homeostasis, but how mitophagy is regulated is largely unknown. Here we found that the kinase Jnk2 was required for stress-induced mitophagy. Jnk2 promoted ubiquitination and proteasomal degradation of the small mitochondrial form of the tumor suppressor ARF (smARF). Loss of Jnk2 led to the accumulation of smARF, which induced excessive autophagy that resulted in lysosomal degradation of the mitophagy adaptor p62 at steady state. Depletion of p62 prevented Jnk2-deficient cells from mounting mitophagy upon stress. Jnk2-deficient mice displayed defective mitophagy, which resulted in tissue damage under hypoxic stress, as well as hyperactivation of inflammasomes and increased mortality in sepsis. Our findings define a unique mechanism of maintaining immunological homeostasis that protects the host from tissue damage and mortality.

Publication types

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

MeSH terms

  • Animals
  • Cells, Cultured
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism*
  • DNA Damage / physiology
  • Female
  • Hypoxia / immunology*
  • Inflammasomes / metabolism
  • Lipopolysaccharides / administration & dosage
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase 9 / genetics
  • Mitogen-Activated Protein Kinase 9 / metabolism*
  • Mitophagy / genetics
  • Proteasome Endopeptidase Complex / metabolism*
  • Proteolysis
  • Proto-Oncogene Proteins c-myc / metabolism
  • Sepsis / chemically induced
  • Sepsis / immunology*
  • Ubiquitination


  • Cdkn2a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p16
  • Inflammasomes
  • Lipopolysaccharides
  • Proto-Oncogene Proteins c-myc
  • Mitogen-Activated Protein Kinase 9
  • Proteasome Endopeptidase Complex