A Bystander Mechanism Explains the Specific Phenotype of a Broadly Expressed Misfolded Protein

Misfolded proteins in transgenic models of conformational diseases interfere with proteostasis machinery and compromise the function of many structurally and functionally unrelated metastable proteins. This collateral damage to cellular proteins has been termed 'bystander' mechanism. How a...

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Bibliographic Details
Published in:	PLoS genetics Vol. 12; no. 12; p. e1006450
Main Authors:	Klabonski, Lauren, Zha, Ji, Senthilkumar, Lakshana, Gidalevitz, Tali
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 01-12-2016 Public Library of Science (PLoS)
Subjects:	Alzheimer's disease Alzheimers disease Animals Biology Biology and Life Sciences Biosynthesis Bystander Effect - genetics Caenorhabditis elegans - genetics Caenorhabditis elegans - growth & development Caenorhabditis elegans Proteins - biosynthesis Caenorhabditis elegans Proteins - chemistry Caenorhabditis elegans Proteins - genetics Cancer Diabetes Gene Expression Regulation, Developmental Genotype & phenotype Growth factors Insulins - biosynthesis Insulins - chemistry Insulins - genetics Larva - genetics Larva - growth & development Localization Mutation Neurons - metabolism Neurons - pathology Phenotype Protein Folding Receptor, Insulin - genetics Research and Analysis Methods Transforming Growth Factor beta - biosynthesis Transforming Growth Factor beta - chemistry Transforming Growth Factor beta - genetics United States > US Pennsylvania
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Summary:	Misfolded proteins in transgenic models of conformational diseases interfere with proteostasis machinery and compromise the function of many structurally and functionally unrelated metastable proteins. This collateral damage to cellular proteins has been termed 'bystander' mechanism. How a single misfolded protein overwhelms the proteostasis, and how broadly-expressed mutant proteins cause cell type-selective phenotypes in disease are open questions. We tested the gain-of-function mechanism of a R37C folding mutation in an endogenous IGF-like C.elegans protein DAF-28. DAF-28(R37C) is broadly expressed, but only causes dysfunction in one specific neuron, ASI, leading to a distinct developmental phenotype. We find that this phenotype is caused by selective disruption of normal biogenesis of an unrelated endogenous protein, DAF-7/TGF-β. The combined deficiency of DAF-28 and DAF-7 biogenesis, but not of DAF-28 alone, explains the gain-of-function phenotype-deficient pro-growth signaling by the ASI neuron. Using functional, fluorescently-tagged protein, we find that, in animals with mutant DAF-28/IGF, the wild-type DAF-7/TGF-β is mislocalized to and accumulates in the proximal axon of the ASI neuron. Activation of two different branches of the unfolded protein response can modulate both the developmental phenotype and DAF-7 mislocalization in DAF-28(R37C) animals, but appear to act through divergent mechanisms. Our finding that bystander targeting of TGF-β explains the phenotype caused by a folding mutation in an IGF-like protein suggests that, in conformational diseases, bystander misfolding may specify the distinct phenotypes caused by different folding mutations.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Conceived and designed the experiments: LK JZ TG.Performed the experiments: LK JZ LS TG.Analyzed the data: LK JZ LS TG.Wrote the paper: LK TG. The authors have declared that no competing interests exist. Current address: Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
ISSN:	1553-7404 1553-7390 1553-7404
DOI:	10.1371/journal.pgen.1006450