title: A Differentiation Transcription Factor Establishes Muscle-Specific Proteostasis in Caenorhabditis elegans.
abstract: 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.
authors.affiliation: Department of Life Sciences and The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: Bar-Lavan
authors.affiliation: Department of Life Sciences and The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva, Israel.
authors.forename: Netta
authors.initials: N
authors.lastname: Shemesh
authors.affiliation: Department of Life Sciences and The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva, Israel.
authors.forename: Shiran
authors.initials: S
authors.lastname: Dror
authors.affiliation: Regenerative Medicine and Stem Cell Research Center, Ben-Gurion University of the Negev, Beer Sheva, Israel.
authors.forename: Rivka
authors.initials: R
authors.lastname: Ofir
authors.affiliation: Department of Clinical Biochemistry and Pharmacology and The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva, Israel.
authors.forename: Esti
authors.identifier: http://orcid.org/0000-0002-8279-7898
authors.initials: E
authors.lastname: Yeger-Lotem
authors.affiliation: Department of Life Sciences and The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva, Israel.
authors.forename: Anat
authors.identifier: http://orcid.org/0000-0003-2477-6519
authors.initials: A
authors.lastname: Ben-Zvi
mesh_terms: D000818:Animals; D001665:Binding Sites; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000254:growth & development; D029742:Caenorhabditis elegans Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D047108:Embryonic Development / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics*; D018832:Molecular Chaperones / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D032342:Muscle Cells / Q000378:metabolism; D024510:Muscle Development / Q000235:genetics; D009124:Muscle Proteins; D018006:Myogenic Regulatory Factors / Q000235:genetics* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic; D014157:Transcription Factors
chemical_list: D029742:Caenorhabditis elegans Proteins; C510188:DAF-21 protein, C elegans; D004268:DNA-Binding Proteins; C485565:DNAJB6 protein, human; D050956:HSP40 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D009124:Muscle Proteins; D018006:Myogenic Regulatory Factors; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; C461262:hsp-12.2 protein, C elegans; C066645:HLH-1 protein, C elegans