Nuclear receptor signaling via NHR-49/MDT-15 regulates stress resilience and proteostasis in response to reproductive and metabolic cues
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Abstract
The ability to sense and respond to proteotoxic insults declines with age, leaving cells vulnerable to chronic and acute stressors. Reproductive cues modulate this decline in cellular proteostasis to influence organismal stress resilience in C. elegans . We previously uncovered a pathway that links the integrity of developing embryos to somatic health in reproductive adults. Here, we show that the nuclear receptor NHR-49, a functional homolog of mammalian peroxisome proliferator-activated receptor alpha (PPARα), regulates stress resilience and proteostasis downstream of embryo integrity and other pathways that influence lipid homeostasis, and upstream of HSF-1. Disruption of the vitelline layer of the embryo envelope, which activates a proteostasis-enhancing inter-tissue pathway in somatic tissues, also triggers changes in lipid catabolism gene expression that are accompanied by an increase in fat stores. NHR-49 together with its co-activator MDT-15 contributes to this remodeling of lipid metabolism and is also important for the elevated stress resilience mediated by inhibition of the embryonic vitelline layer as well as by other pathways known to change lipid homeostasis, including reduced insulin-like signaling and fasting. Further, we show that increased NHR-49 activity is sufficient to suppress polyglutamine aggregation and improve stress resilience in an HSF-1-dependent manner. Together, our results establish NHR-49 as a key regulator that links lipid homeostasis and cellular resilience to proteotoxic stress.
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Direct interaction of NHR-49/MDT-15 with HSF-1 or binding to a nearbymotif may thus facilitate the recruitment of the transcription machinery to heat shock genes duringproteotoxic stress
In general, NHR recruitment of coactivators or corepressors is regulated by the position of the terminal helix 12 of the ligand binding domain. Helix 12 is necessary for the proper confirmation of NHR to recruit coactivators, while it is dispensable for recruitment of corepressors. In fact, amputation of NHRs which remove helix 12 convert the receptors into constitutive repressors. While a corepressor for nhr-49 has not been identified, it may be revealing to generate an nhr-49 allele that lacks helix 12. It would be unlikely to bind MDT-15 and may help dissect mdt-15 roles in regulating *hsf-1 *function, as well the cement the role of mdt-15 in nhr-49…
Direct interaction of NHR-49/MDT-15 with HSF-1 or binding to a nearbymotif may thus facilitate the recruitment of the transcription machinery to heat shock genes duringproteotoxic stress
In general, NHR recruitment of coactivators or corepressors is regulated by the position of the terminal helix 12 of the ligand binding domain. Helix 12 is necessary for the proper confirmation of NHR to recruit coactivators, while it is dispensable for recruitment of corepressors. In fact, amputation of NHRs which remove helix 12 convert the receptors into constitutive repressors. While a corepressor for nhr-49 has not been identified, it may be revealing to generate an nhr-49 allele that lacks helix 12. It would be unlikely to bind MDT-15 and may help dissect mdt-15 roles in regulating *hsf-1 *function, as well the cement the role of mdt-15 in nhr-49 mediated regulation of proteotoxic stress.
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Together, the data presented in this study suggests that NHR-49, through its lipid sensing and gene regulatory function, represents a link between lipidmetabolism and regulation of the HSR via modulation of HSF-1 activity (Fig. 5G)
I appreciate the clarity in Figure 5G, but it may be helpful to include all of the genes/proteins involved in this pathway that were mentioned above, to aid in interpreting your conclusions.
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The partialsuppression of nhr-49 was likely due incomplete penetrance of the RNAi since the loss-of-functionallele nhr-49(nr2041) nearly completely abrogated the beneficial effects of cbd-1(ok2913) on heatstress survival (Fig. 3F)
It appears that there is a significant difference between the percent survival of wild type worms + control RNAi (Fig 3F) and wild type worms (Fig 3G) as well as cdb-1 + control RNAi (Fig 3F) and* cdb-1* (Fig 3G). Is this difference due to the different bacteria used for dsRNA expression and normal growth, for instance, HT115 vs. OP50, or some other variation?
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Wefound that RNAi knockdown of mdt-15 completely suppressed and nhr-49 significantly reducedthe prolonged survival of cbd-1(ok2913) following a lethal heat stress (Fig. 3F)
This is an elegant study implicating nhr-49 as an important link tying lipid metabolism to proteotoxic stress. I only had a few questions. Since mediator is a shared coactivator used by numerous transcription factors, could the difference in suppression be due to med-15 targets that are not regulated by nhr-49? And do you know if *mdt-15 *RNAi recapitulates a null allele of mdt-15?
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