Ubiquitin-like protein 5 positively regulates chaperone gene expression in the mitochondrial unfolded protein response.
Perturbation of the protein-folding environment in the mitochondrial matrix selectively upregulates the expression of nuclear genes encoding mitochondrial chaperones. To identify components of the signal transduction pathway(s) mediating this mitochondrial unfolded protein response (UPR(mt)), we first isolated a temperature-sensitive mutation (zc32) that conditionally activates the UPR(mt) in C. elegans and subsequently searched for suppressors by systematic inactivation of genes. RNAi of ubl-5, a gene encoding a ubiquitin-like protein, suppresses activation of the UPR(mt) markers hsp-60::gfp and hsp-6::gfp by the zc32 mutation and by other manipulations that promote mitochondrial protein misfolding. ubl-5 (RNAi) inhibits the induction of endogenous mitochondrial chaperone encoding genes hsp-60 and hsp-6 and compromises the ability of animals to cope with mitochondrial stress. Mitochondrial morphology and assembly of multi-subunit mitochondrial complexes of biotinylated proteins are also perturbed in ubl-5(RNAi) worms, indicating that UBL-5 also counteracts physiological levels of mitochondrial stress. Induction of mitochondrial stress promotes accumulation of GFP-tagged UBL-5 in nuclei of transgenic worms, suggesting that UBL-5 effects a nuclear step required for mounting a response to the threat of mitochondrial protein misfolding.
Benedetti
Cristina
C
Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York 10016, USA.
Haynes
Cole M
CM
Yang
Yun
Y
Harding
Heather P
HP
Ron
David
D
D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism*; D008954:Models, Biological; D018832:Molecular Chaperones / Q000378:metabolism*; D009154:Mutation; D017510:Protein Folding; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000009:adverse effects; D014018:Tissue Distribution / Q000187:drug effects; D014452:Ubiquitins / Q000378:metabolism* / Q000502:physiology
D029742:Caenorhabditis elegans Proteins; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones; D034741:RNA, Small Interfering; D014452:Ubiquitins; C515527:Ubl-5 protein, C elegans