Activating transcription factor 4 (ATF4) promotes skeletal muscle atrophy by forming a heterodimer with the transcriptional regulator C/EBPβ

J Biol Chem. 2020 Feb 28;295(9):2787-2803. doi: 10.1074/jbc.RA119.012095. Epub 2020 Jan 17.


Skeletal muscle atrophy is a highly-prevalent and debilitating condition that remains poorly understood at the molecular level. Previous work found that aging, fasting, and immobilization promote skeletal muscle atrophy via expression of activating transcription factor 4 (ATF4) in skeletal muscle fibers. However, the direct biochemical mechanism by which ATF4 promotes muscle atrophy is unknown. ATF4 is a member of the basic leucine zipper transcription factor (bZIP) superfamily. Because bZIP transcription factors are obligate dimers, and because ATF4 is unable to form highly-stable homodimers, we hypothesized that ATF4 may promote muscle atrophy by forming a heterodimer with another bZIP family member. To test this hypothesis, we biochemically isolated skeletal muscle proteins that associate with the dimerization- and DNA-binding domain of ATF4 (the bZIP domain) in mouse skeletal muscle fibers in vivo Interestingly, we found that ATF4 forms at least five distinct heterodimeric bZIP transcription factors in skeletal muscle fibers. Furthermore, one of these heterodimers, composed of ATF4 and CCAAT enhancer-binding protein β (C/EBPβ), mediates muscle atrophy. Within skeletal muscle fibers, the ATF4-C/EBPβ heterodimer interacts with a previously unrecognized and evolutionarily conserved ATF-C/EBP composite site in exon 4 of the Gadd45a gene. This three-way interaction between ATF4, C/EBPβ, and the ATF-C/EBP composite site activates the Gadd45a gene, which encodes a critical mediator of muscle atrophy. Together, these results identify a biochemical mechanism by which ATF4 induces skeletal muscle atrophy, providing molecular-level insights into the etiology of skeletal muscle atrophy.

Keywords: CCAAT enhancer-binding protein β (C/EBPβ); activating transcription factor 4 (ATF4); basic leucine zipper transcription factor (bZIP); gene regulation; growth arrest and DNA damage-inducible α (Gadd45α); muscle; muscle atrophy; protein–DNA interaction; protein–protein interaction; skeletal muscle.

Publication types

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

MeSH terms

  • Activating Transcription Factor 4 / metabolism*
  • Activating Transcription Factors / metabolism
  • Animals
  • CCAAT-Enhancer-Binding Protein-beta / metabolism*
  • Cell Cycle Proteins / genetics
  • Mice
  • Muscle, Skeletal / pathology
  • Muscular Atrophy / etiology*
  • Protein Multimerization*


  • Activating Transcription Factors
  • Atf4 protein, mouse
  • CCAAT-Enhancer-Binding Protein-beta
  • Cebpb protein, mouse
  • Cell Cycle Proteins
  • Gadd45a protein, mouse
  • Activating Transcription Factor 4