A Differentiation Transcription Factor Establishes Muscle-Specific Proteostasis in Caenorhabditis elegans

PLoS Genet. 2016 Dec 30;12(12):e1006531. doi: 10.1371/journal.pgen.1006531. eCollection 2016 Dec.


Safeguarding the proteome is central to the health of the cell. In multi-cellular organisms, the composition of the proteome, and by extension, protein-folding requirements, varies between cells. In agreement, chaperone network composition differs between tissues. Here, we ask how chaperone expression is regulated in a cell type-specific manner and whether cellular differentiation affects chaperone expression. Our bioinformatics analyses show that the myogenic transcription factor HLH-1 (MyoD) can bind to the promoters of chaperone genes expressed or required for the folding of muscle proteins. To test this experimentally, we employed HLH-1 myogenic potential to genetically modulate cellular differentiation of Caenorhabditis elegans embryonic cells by ectopically expressing HLH-1 in all cells of the embryo and monitoring chaperone expression. We found that HLH-1-dependent myogenic conversion specifically induced the expression of putative HLH-1-regulated chaperones in differentiating muscle cells. Moreover, disrupting the putative HLH-1-binding sites on ubiquitously expressed daf-21(Hsp90) and muscle-enriched hsp-12.2(sHsp) promoters abolished their myogenic-dependent expression. Disrupting HLH-1 function in muscle cells reduced the expression of putative HLH-1-regulated chaperones and compromised muscle proteostasis during and after embryogenesis. In turn, we found that modulating the expression of muscle chaperones disrupted the folding and assembly of muscle proteins and thus, myogenesis. Moreover, muscle-specific over-expression of the DNAJB6 homolog DNJ-24, a limb-girdle muscular dystrophy-associated chaperone, disrupted the muscle chaperone network and exposed synthetic motility defects. We propose that cellular differentiation could establish a proteostasis network dedicated to the folding and maintenance of the muscle proteome. Such cell-specific proteostasis networks can explain the selective vulnerability that many diseases of protein misfolding exhibit even when the misfolded protein is ubiquitously expressed.

MeSH terms

  • Animals
  • Binding Sites
  • Caenorhabditis elegans / genetics*
  • Caenorhabditis elegans / growth & development
  • Caenorhabditis elegans Proteins / biosynthesis
  • Caenorhabditis elegans Proteins / genetics*
  • Caenorhabditis elegans Proteins / metabolism
  • Cell Differentiation / genetics
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Embryonic Development / genetics
  • Gene Expression Regulation, Developmental
  • HSP40 Heat-Shock Proteins / genetics
  • HSP40 Heat-Shock Proteins / metabolism
  • HSP90 Heat-Shock Proteins / genetics*
  • HSP90 Heat-Shock Proteins / metabolism
  • Heat-Shock Proteins / biosynthesis
  • Heat-Shock Proteins / genetics*
  • Molecular Chaperones / biosynthesis
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism
  • Muscle Cells / metabolism
  • Muscle Development / genetics
  • Muscle Proteins
  • Myogenic Regulatory Factors / genetics*
  • Myogenic Regulatory Factors / metabolism
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Nuclear Proteins
  • Promoter Regions, Genetic
  • Transcription Factors


  • Caenorhabditis elegans Proteins
  • DAF-21 protein, C elegans
  • DNA-Binding Proteins
  • DNAJB6 protein, human
  • HSP40 Heat-Shock Proteins
  • HSP90 Heat-Shock Proteins
  • Heat-Shock Proteins
  • Molecular Chaperones
  • Muscle Proteins
  • Myogenic Regulatory Factors
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Transcription Factors
  • hsp-12.2 protein, C elegans
  • HLH-1 protein, C elegans

Grant support

This research was supported by a grant from the Israel Science Foundation (ABZ, grant No. 91/11; https://www.isf.org.il/#/) and by the Legacy Heritage Biomedical Science Partnership Program of the Israel Science Foundation (ABZ, grant No. 804/13; https://www.isf.org.il/#/). EYL was supported by a grant from the Israel Science Foundation (EYL, grant No. 860/13; https://www.isf.org.il/#/). YBL was supported by Kreitman short-term post-doctoral scholarship. NS was supported by Kreitman Negev scholarship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.