Host cell factor 1 inhibits SKN-1 to modulate oxidative stress responses in Caenorhabditis elegans.

Host cell factor-1 (HCF-1) is a conserved regulator of the longevity and stress response functions of DAF-16/FOXO. SKN-1 transcription factor is an evolutionarily conserved xenobiotic stress regulator and a pro-longevity factor. Here, we demonstrate that SKN-1 contributes to the enhanced oxidative stress resistance incurred by hcf-1 mutation in C. elegans. HCF-1 prevents the nuclear accumulation of SKN-1 and represses the transcriptional activation of SKN-1 specifically at target genes involved in cellular detoxification pathways. Our findings reveal a novel and context-specific regulatory relationship between two highly conserved longevity and stress response factors HCF-1 and SKN-1.

Rizki G ，Picard CL ，Pereyra C ，Lee SS ... -  《-》

Caenorhabditis elegans HCF-1 functions in longevity maintenance as a DAF-16 regulator.

Li J ，Ebata A ，Dong Y ，Rizki G ，Iwata T ，Lee SS ... -  《-》

The evolutionarily conserved longevity determinants HCF-1 and SIR-2.1/SIRT1 collaborate to regulate DAF-16/FOXO.

Rizki G ，Iwata TN ，Li J ，Riedel CG ，Picard CL ，Jan M ，Murphy CT ，Lee SS ... -  《PLoS Genetics》

The conserved Mediator subunit MDT-15 is required for oxidative stress responses in Caenorhabditis elegans.

Reactive oxygen species (ROS) play important signaling roles in metazoans, but also cause significant molecular damage. Animals tightly control ROS levels using sophisticated defense mechanisms, yet the transcriptional pathways that induce ROS defense remain incompletely understood. In the nematode Caenorhabditis elegans, the transcription factor SKN-1 is considered a master regulator for detoxification and oxidative stress responses. Here, we show that MDT-15, a subunit of the conserved Mediator complex, is also required for oxidative stress responses in nematodes. Specifically, mdt-15 is required to express SKN-1 targets upon chemical and genetic increase in SKN-1 activity. mdt-15 is also required to express genes in SKN-1-dependent and SKN-1-independent fashions downstream of insulin/IGF-1 signaling and for the longevity of daf-2/insulin receptor mutants. At the molecular level, MDT-15 binds SKN-1 through a region distinct from the classical transcription-factor-binding KIX-domain. Moreover, mdt-15 is essential for the transcriptional response to and survival on the organic peroxide tert-butyl-hydroperoxide (tBOOH), a largely SKN-1-independent response. The MDT-15 interacting nuclear hormone receptor, NHR-64, is specifically required for tBOOH but not arsenite resistance, but NHR-64 is dispensable for the transcriptional response to tBOOH. Hence, NHR-64 and MDT-15's mode of action remain elusive. Lastly, the role of MDT-15 in oxidative stress defense is functionally separable from its function in fatty acid metabolism, as exogenous polyunsaturated fatty acid complementation rescues developmental, but not stress sensitivity phenotypes of mdt-15 worms. Our findings reveal novel conserved players in the oxidative stress response and suggest a broad cytoprotective role for MDT-15.

Goh GY ，Martelli KL ，Parhar KS ，Kwong AW ，Wong MA ，Mah A ，Hou NS ，Taubert S ... -  《-》

SKN-1 Is a Negative Regulator of DAF-16 and Somatic Stress Resistance in Caenorhabditis elegans.

The transcription factor SKN-1, the C. elegans ortholog of mammalian Nrf protein, is a well-known longevity factor, and its activation is observed in several long-lived models. SKN-1 also plays essential roles in xenobiotic and oxidative stress responses. Here, we report deleterious functions of SKN-1 in somatic stress resistance that may impair lifespan. Constitutive SKN-1 activation impairs animal resistance to several stresses, including heat, ER stress and mitochondrial stress, which result from the suppression of DAF-16, another master regulator of longevity. SKN-1 activation abrogates DAF-16 nuclear import and downregulates DAF-16 target genes under stress conditions, while SKN-1 inhibition promotes the expression of DAF-16 targets, even in long-lived mutants. Further, SKN-1 activation induces the expression of vitellogenin proteins, which are required for SKN-1-mediated suppression of DAF-16 and stress resistance. Together, these findings identify detrimental roles for SKN-1 activation in animal health, and more importantly, inspire the rethinking of the complex roles for SKN-1 in aging regulation.

Deng J ，Dai Y ，Tang H ，Pang S ... -  《G3-Genes Genomes Genetics》