Yuan, Wang et al. (2021) International Worm Meeting "Wide-Spread Non-Canonical CED-3 Caspase Activities Regulate Gene Expression Dynamics Including Antagonizing PMK-1 p38 MAPK Stress-Priming Function to Support Development"

Yuan, Wang, Weaver, Benjamin, Weaver, Yi

[International Worm Meeting, 2021]

Recent studies across diverse animal phyla have revealed non-canonical activities of apoptotic caspases involving specific modulation of gene expression, such as our finding of LIN-28 inactivation in worms and others findings of Nanog and Pax7 inactivation in mice to limit pluripotency of stem-like cell types to promote differentiation. We still do not know how broadly these non-canonical caspase functions span across various biological processes or their underlying molecular mechanisms. Using a forward genetic screen, we identified the CED-3 caspase working in diverse biological processes in C. elegans. Specifically, we recently showed that CED-3 caspase negatively regulates an epidermal p38 stress-responsive MAPK pathway to promote development. We also showed that PMK-1 (p38 MAPK) functions to prime animals for adverse environmental conditions prior to experiencing the stress. However, this priming function comes with the cost of retarding post-embryonic development. CED-3 caspase counters this stress-priming function by inactivating PMK-1 through proteolytic cleavage thereby promoting development. Strikingly, using RNA-seq and ribosomal profiling, we find that CED-3 and PMK-1 inversely regulate a key sub-set of more than 300 genes. A key enrichment amongst these genes were stress-responsive and pathogen resistance factors. Now, our ongoing studies are working to identify the molecular and physiological mechanisms of CED-3 and PMK-1 antagonism in regulating cell signaling and gene expression dynamics during development and stress-response states.

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.

Hoskins R (1987) Worm Breeder's Gazette "unc-30 on the map."

Hoskins R

[Worm Breeder's Gazette, 1987]

The unc-30 gene has been found to lie on the physical map, in a contig previously shown by J. Yuan to span the ced-3 locus(CSH 1987). unc-30 recombinants were picked from the progeny of unc-31(e928)unc- 30(e191)/BO parents and used to map BO/N2 DNA polymorphisms found in the ced-3 contig. The data indicate that unc-30 is surprisingly close to ced-3.Two polymorphisms have been mapped. They have been designated eP56 and eP57, and are recognized by hybridization with the cosmids ZK987 and C43A2, respectively. They map as follows: unc- 31[8]eP56[4]ePS[1]unc-30. A right-hand limit on the position of unc- 30 has been established by Yuan. She has mapped a BO-specific Tc1 to the right of ced-3 in the cosmid MMMC1. The physical distance between unc-30 and ced-3 must therefore be less than 120kb of DNA; the genetic distance between them is 0.3-0.5%. It should now be possible to clone the unc-30 gene. Attempts toward this end have been hampered by the potpourri of repeat sequences in cosmids to the right of eP57. Several DNA polymorphisms have been found in EMS, [32P], and spontaneous BO unc-30 alleles.

Matsumoto M et al. (2005) Cell Metab "All roads lead to FoxO."

Accili D, Matsumoto M

[Cell Metab, 2005]

Stress-activated kinases control metabolism by antagonizing the early steps of insulin signal transduction. Two papers now demonstrate that Jnk, the prototypical stress-activated kinase, controls life span in Drosophila and C. elegans by promoting phosphorylation of the forkhead protein FoxO (Oh et al., 2005; Wang et al., 2005). The findings provide yet another mechanism by which metabolic and stress responses are integrated via phosphorylation of FoxO proteins.