Wang, Xi et al. (2009) International Worm Meeting "The 3-b-hydroxysteroid dehydrogenase (3bHSD) family member HSD-1 controls dauer arrest via regulation of nuclear DAF-16/FoxO."

Hu, Patrick J., Wang, Xi, Guo, Chunfang, Dumas, Kathleen, Adams, Elizabeth, Burkhart, Kirk, Alam, Hena

[International Worm Meeting, 2009]

The C. elegans insulin receptor ortholog DAF-2 promotes reproductive development and controls lifespan by regulating nuclear translocation of the FoxO transcription factor DAF-16 via a conserved PI 3-kinase/Akt pathway. Nuclear localization of DAF-16/FoxO is necessary but not sufficient for full DAF-16/FoxO activity, suggesting that other inputs regulate the activity of nuclear DAF-16/FoxO. We recently discovered the EAK (enhancer-of-akt-1) pathway, which acts in parallel to AKT-1 to inhibit nuclear DAF-16/FoxO activity. eak-2 is allelic to hsd-1, which encodes a conserved 3bHSD family member thought to participate with the cytochrome P450 DAF-9 in the biosynthesis of steroids known as dafachronic acids (DAs). DAs function as ligands for the nuclear receptor DAF-12. As is the case for other eak mutants, hsd-1 and daf-9 mutations enhance the dauer arrest phenotype of an akt-1 null mutation, suggesting that the EAK pathway regulates DA action and that DAs act in parallel to AKT-1 to promote reproductive development. hsd-1 mutations enhance the dauer arrest phenotype of akt-1 mutants and increase mRNA levels of the direct DAF-16/FoxO target gene sod-3 in akt-1 mutants in a DAF-16/FoxO- and DAF-12-dependent manner. In contrast to akt-1 mutation, hsd-1 mutation does not promote DAF-16::GFP nuclear localization. Furthermore, hsd-1 mutation enhances the dauer arrest phenotype of a strain expressing a constitutively nuclear DAF-16::GFP fusion protein that lacks all consensus AKT-1 phosphorylation sites, suggesting that HSD-1 regulates the activity of nuclear DAF-16/FoxO. Taken together, our results support a model whereby HSD-1 and AKT-1 act via distinct and complementary mechanisms to promote reproductive development by regulating the expression of a subset of DAF-16/FoxO target genes. Although hsd-1 mutants have normal lifespans, HSD-1 activity is required for lifespan extension in mutants with reduced DAF-2 pathway signaling, suggesting that HSD-1 and DAs may modulate DAF-2 pathway signaling in a context-dependent manner.

Xi Wang et al. (2007) International Worm Meeting "Role of the 3-b-hydroxysteroid dehydrogenase homolog hsd-1/eak-2 in steroid regulation of C. elegans dauer formation."

David Mangelsdorf, Weiqing Li, Kirk Burkhart, Xi Wang, Patrick J. Hu, Zhu Wang

[International Worm Meeting, 2007]

Conserved insulin-like and hormonal signaling pathways regulate development and longevity in C. elegans. The molecular interface between these two pathways remains poorly characterized. We identified eak-2 (enhancer-of-akt-1) in a genetic screen for novel components of insulin-like signaling. Genetic analysis indicates that eak-2 functions in parallel to akt-1 to inhibit daf-16/FoxO. eak-2 is allelic to hsd-1, which encodes a protein with homology to 3-<font face=symbol>b</font>-hydroxysteroid dehydrogenases. hsd-1/eak-2 is expressed specifically in the two neuroendocrine XXX cells. 4-cholesten-3-one, a potential product of HSD-1/EAK-2 and a substrate of DAF-9 for the synthesis of the DAF-12 ligand <font face=symbol>D</font>4-dafachronic acid, rescues the dauer arrest phenotype of hsd-1/eak-2 mutants, supporting the role of a steroidogenic pathway in dauer regulation. Our results suggest that HSD-1/EAK-2 functions in both insulin-like and hormonal pathways to regulate dauer arrest. We are using a cell transfection assay and an in vitro microsomal assay to confirm the enzymatic activity of HSD-1/EAK-2 and dissect its relationship with other known components of the hormonal dauer regulatory pathway. We are also investigating the effect of hsd-1/eak-2 mutation on DAF-16/FoxO activity in vivo.

Xi Wang et al. (2008) C.elegans Aging, Stress, Pathogenesis, and Heterochrony Meeting "The 3-beta-Hydroxysteroid Dehydrogenase (3betaHSD) Family Member HSD-1/EAK-2 Acts in the Dafachronic Acid Biosynthetic Pathway to Inhibit Nuclear DAF-16/FoxO Activity"

Shengying Li, Yousong Ding, Kirk Burkhart, David Sherman, Patrick Hu, Hena Alam, Xi Wang

[C.elegans Aging, Stress, Pathogenesis, and Heterochrony Meeting, 2008]

How transcription factors interact functionally to regulate dauer arrest is poorly understood. The EAK pathway promotes reproductive development by acting in parallel to AKT-1 to inhibit the activity of the FoxO transcription factor DAF-16. eak-2 is allelic to the conserved 3betaHSD family member hsd-1, which was first identified as an enhancer of the ncr-1 dauer arrest phenotype. In contrast to AKT-1, which promotes the cytoplasmic retention of DAF-16/FoxO, HSD-1 does not affect DAF-16/FoxO subcellular localization but inhibits nuclear DAF-16/FoxO activity. In hsd-1;akt-1 double mutants, both DAF-16/FoxO and DAF-12 are required for maximal expression of the direct DAF-16/FoxO target gene sod-3. Preliminary results suggest that HSD-1 has 3betaHSD activity in vitro. We propose that HSD-1 acts in parallel to AKT-1 to regulate the expression of a subset of DAF-16/FoxO target genes via dafachronic acids and DAF-12. 3betaHSD family members may interact similarly with insulin signaling to regulate FoxO target gene expression in mammals.

Infarinato N (2019) J Cell Biol "Xiaochen Wang: Building up our understanding of breaking down."

Infarinato N

[J Cell Biol, 2019]

Wang studies lysosomal degradation pathways using <i>C. elegans</i> as a model system.

Wang JT et al. (2014) Curr Biol "P granules."

Seydoux G, Wang JT

[Curr Biol, 2014]

Wang and Seydoux discuss the functional importance of P granules - the germline-specific RNA granules of C. elegans.

Munro E (2017) Dev Cell "Protein Clustering Shapes Polarity Protein Gradients."

Munro E

[Dev Cell, 2017]

In this issue of Developmental Cell, Dickinson etal. (2017) and Rodriguez etal. (2017), along with Wang etal. (2017) in Nature Cell Biology, show how PAR protein oligomerization can dynamically couple protein diffusion and transport by cortical flow to control kinase activity gradients and polarity in the C.elegans zygote.

Rashid S et al. (2017) Dev Cell "Packing on the Pounds in Response to Bacterial Growth Conditions."

Rashid S, MacNeil LT

[Dev Cell, 2017]

Reporting in Nature Cell Biology, Lin and Wang (2017) show that bacterial methyl metabolism impacts host mitochondrial dynamics and lipid storage in C.elegans. The authors propose a model whereby bacterial metabolic products regulate a nuclear hormone receptor that promotes lipid accumulation through expression of a secreted Hedgehog-like protein.

Vincenz L et al. (2014) Cell "Sugarcoating ER Stress."

Vincenz L, Hartl FU

[Cell, 2014]

The hexosamine biosynthetic pathway (HBP) generates metabolites for protein N- and O-glycosylation. Wang et al. and Denzel et al. report a hitherto unknown link between the HBP and stress in the endoplasmic reticulum. These studies establish the HBP as a critical component of the cellular machinery of protein homeostasis.

Sural S (2023) Trends Genet "Protecting axons in grandchildren."

Sural S

[Trends Genet, 2023]

Prenatal exposure to environmental agents can influence the fitness of not only the fetus, but also subsequent generations. In a recent study, Wang et al. demonstrated that feeding ursolic acid (UA), a plant-derived compound, to Caenorhabditis elegans mothers during their reproductive period prevented neurodegeneration in not only their offspring, but also the F2 progeny.

Spalthoff C et al. (2016) Neuron "Sensing pH with TMCs."

Gopfert MC, Spalthoff C

[Neuron, 2016]

Transmembrane channel-like (TMC) proteins have been implicated in hair cell mechanotransduction, Drosophila proprioception, and sodium sensing in the nematode C.elegans. In this issue of Neuron, Wang etal. (2016) report that C.elegans TMC-1 mediates nociceptor responses to high pH, not sodium, allowing the nematode to avoid strongly alkaline environments in which most animals cannot survive.