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Abstract
Thioredoxins comprise a conserved family of redox regulators involved in many biological processes, including stress resistance and aging. We report that the C. elegans thioredoxin TRX-1 acts in ASJ head sensory neurons as a novel modulator of the insulin-like neuropeptide DAF-28 during dauer formation. We show that increased formation of stress-resistant, long-lived dauer larvae in mutants for the gene encoding the insulin-like neuropeptide DAF-28 requires TRX-1 acting in ASJ neurons, upstream of the insulin-like receptor DAF-2. Genetic rescue experiments demonstrate that redox-independent functions of TRX-1 specifically in ASJ neurons are needed for the dauer formation constitutive (Daf-c) phenotype of daf-28 mutants. GFP reporters of trx-1 and daf-28 show opposing expression patterns in dauers (i.e. trx-1 is up-regulated and daf-28 is down-regulated), an effect that is not observed in growing L2/L3 larvae. In addition, functional TRX-1 is required for the down-regulation of a GFP reporter of daf-28 during dauer formation, a process that is likely subject to DAF-28-mediated feedback regulation. Our findings demonstrate that TRX-1 modulates DAF-28 signaling by contributing to the down-regulation of daf-28 expression during dauer formation. We propose that TRX-1 acts as a fluctuating neuronal signaling modulator within ASJ neurons to monitor the adjustment of neuropeptide expression, including insulin-like proteins, during dauer formation in response to adverse environmental conditions.
Highlights
Thioredoxins comprise a conserved family of proteins characterized by the so-called thioredoxin fold and the highly conserved cysteine–glycine–proline–cysteine (CGPC) catalytic active site
This dual effect of the trx-1 mutation on daf-11 for dauer formation is reminiscent, not identical, to that reported for mutations in the cyclic guanosine monophosphate (cGMP)-gated ion channel genes tax-2 and tax-4 [16]. tax-2 and tax-4 mutants show weak dauer formation constitutive (Daf-c) phenotypes, which are epistatic to the strong daf-11 Daf-c phenotypes [16]. trx-1 deletion did not affect the weak Daf-c phenotype caused by tax-4(p678) (Figures 1A and 1B; Tables 1 and 2)
We found that trx-1 suppresses the Daf-c phenotypes of all daf-28 insulin-like mutant alleles tested, and that this suppression is dependent on a functional DAF-2 insulin-like receptor (Figures 1A and 1B; Tables 1 and 2)
Summary
Thioredoxins comprise a conserved family of proteins characterized by the so-called thioredoxin fold and the highly conserved cysteine–glycine–proline–cysteine (CGPC) catalytic active site (reviewed in [1,2]). The two cysteines in the active site of thioredoxin are required for the reversible reduction of disulfide bonds in many target proteins. The functions of thioredoxins are extensive and mostly depend on their disulfide oxidoreductase attributes; in general, they can act as electron donors for metabolic enzymes, as antioxidants, or as redox regulators of signaling molecules and transcription factors (reviewed in [1]). Thioredoxins have been reported to execute their specific functions in a redox-independent manner (reviewed in [2,3]). Thioredoxins have been shown to promote folding of proteins independently of their redox activities (reviewed in [3])
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