Liu L et al. (2018) Structure "Regulation of Kinase Activity in the Caenorhabditis elegans EGF Receptor, LET-23."

Liu L, Jura N, Frazier N, Freed DM, Malhotra K, Thaker TM, Lemmon MA

[Structure, 2018]

In the active HER receptor dimers, kinases play distinct roles; one is the catalytically active kinase and the other is its allosteric activator. This specialization enables signaling by the catalytically inactive HER3, which functions exclusively as an allosteric activator upon heterodimerization with other HER receptors. It is unclear whether the allosteric activation mechanism evolved before HER receptors functionally specialized. We determined the crystal structure of the kinase domain of the only EGF receptor in Caenorhabditis elegans, LET-23. Our structure of a non-human EGFR kinase reveals autoinhibitory features conserved in the human counterpart. Strikingly, mutations within the putative allosteric dimer interface abrogate activity of the isolated LET-23 kinase and of the full-length receptor despite these regions being only partially conserved with human EGFR. Our results indicate that ancestral EGFRs have built-in features that poise them for allosteric activation that could facilitate emergence of the catalytically dead, yet functional, orthologs.

Liu L et al. (2023) Sci China Life Sci "Systematic characterization of small RNAs associated with C. elegans Argonautes."

Chen H, Li Q, Zhao W, Liu L, Wang X, Shan G, Li J

[Sci China Life Sci, 2023]

Argonaute proteins generally play regulatory roles by forming complexes with the corresponding small RNAs (sRNAs). An expanded Argonaute family with 20 potentially functional members has been identified in Caenorhabditis elegans. Canonical sRNAs in C. elegans are miRNAs, small interfering RNAs including 22G-RNAs and 26G-RNAs, and 21U-RNAs, which are C. elegans piRNAs. Previous studies have only covered some of these Argonautes for their sRNA partners, and thus, a systematic study is needed to reveal the comprehensive regulatory networks formed by C. elegans Argonautes and their associated sRNAs. We obtained in situ knockin (KI) strains of all C. elegans Argonautes with fusion tags by CRISPR/Cas9 technology. RNA immunoprecipitation against these endogenously expressed Argonautes and high-throughput sequencing acquired the sRNA profiles of individual Argonautes. The sRNA partners for each Argonaute were then analyzed. We found that there were 10 Argonautes enriched miRNAs, 17 Argonautes bound to 22G-RNAs, 8 Argonautes bound to 26G-RNAs, and 1 Argonaute PRG-1 bound to piRNAs. Uridylated 22G-RNAs were bound by four Argonautes HRDE-1, WAGO-4, CSR-1, and PPW-2. We found that all four Argonautes played a role in transgenerational epigenetic inheritance. Regulatory roles of the corresponding Argonaute-sRNA complex in managing levels of long transcripts and interspecies regulation were also demonstrated. In this study, we portrayed the sRNAs bound to each functional Argonaute in C. elegans. Bioinformatics analyses together with experimental investigations provided perceptions in the overall view of the regulatory network formed by C. elegans Argonautes and sRNAs. The sRNA profiles bound to individual Argonautes reported here will be valuable resources for further studies.

Liu L et al. (2018) Genetics "Integration of Stress Signaling in Caenorhabditis elegans Through Cell Non-autonomous Contributions of the JNK Homolog KGB-1."

Shapira M, Ruediger C, Liu L

[Genetics, 2018]

Dealing with physiological stress is a necessity for all organisms, and the pathways charged with this task are highly conserved in metazoa. Accumulating evidence highlights cell non-autonomous activation as an important mode of integrating stress responses at the organism level, and work in <i>Caenorhabditis elegans</i> further highlighted the importance of such regulation for the unfolded protein response (UPR) and for DAF-16-dependent gene expression. Here we describe a role for the JNK homolog KGB-1 in cell non-autonomous regulation of these two response modules. KGB-1 protects developing larvae from protein folding stress (independent of canonical UPR pathways) and heavy metals, but has been shown to sensitize adult animals to the same stress, and to shorten lifespan, in association with an age-dependent antagonistic regulation of the longevity-associated transcription factor DAF-16. Using transgenic animals expressing KGB-1 from different tissue-specific promoters, focusing on tissues relevant for KGB-1-dependent phenotypes, we examined the effects of KGB-1 activation on gene regulation, stress resistance and lifespan. While cell autonomous contributions were observed, especially in the epidermis, KGB-1 largely operated through cell non-autonomous contributions, which mediated gene induction, age-dependent regulation of intestinal DAF-16, and stress resistance, and were mostly independent of KGB-1 expression in the target tissue. Additional genetic analysis revealed requirement for UNC-13 in mediating some of these contributions, indicating involvement of neurotransmission. Our results expand the role of KGB-1 in stress responses from providing local cellular protection, to integrating stress responses at the level of the whole-organism.

Liu L et al. (2011) Biochem Biophys Res Commun "Caenorhabditis elegans ciliary protein NPHP-8, the homologue of human RPGRIP1L, is required for ciliogenesis and chemosensation."

Xia Z, Liu L, Chen L, Xu P, Zhang M, Xu T

[Biochem Biophys Res Commun, 2011]

Nephronophthisis (NPHP) is the most frequent genetic cause of end-stage renal failure in children and young adults. NPHP8/RPGRIP1L is a novel ciliary gene that, when mutated, in addition to causing NPHP, also causes Joubert syndrome (JBTS) and Meckel syndrome (MKS). The exact function of NPHP8 and how defects in NPHP8 lead to human diseases are poorly understood. Here, we studied the Caenorhabditis elegans homolog nphp-8 (C09G5.8) and explored the possible function of NPHP-8 in ciliated sensory neurons. We determined the gene structure of nphp-8 through rapid amplification of cDNA ends (RACE) analysis and discovered an X-box motif that had been previously overlooked. Moreover, NPHP-8 co-localized with NPHP-4 at the transition zone at the base of cilia. Mutation of nphp-8 led to abnormal dye filling (Dyf) and shorter cilia lengths in a subset of ciliary neurons. In addition, chemotaxis to several volatile attractants was significantly impaired in nphp-8 mutants. Our data suggest that NPHP-8/RPGRIP1L plays an important role in cilia formation and cilia-mediated chemosensation in a cell type-specific manner.

Liu L et al. (2023) Int J Mol Sci "Integrated Analysis of Transcriptome and Metabolome Provides Insight into Camellia oleifera Oil Alleviating Fat Accumulation in High-Fat Caenorhabditis elegans."

Kuang X, Chen T, Xiang Z, Zhou L, Liu L, Kong Q, Feng S, Ding C, Wang H

[Int J Mol Sci, 2023]

Camellia oil (CO) is a high medicinal and nutritional value edible oil. However, its ability to alleviate fat accumulation in high-fat <i>Caenorhabditis elegans</i> has not been well elucidated. Therefore, this study aimed to investigate the effect of CO on fat accumulation in high-fat <i>C. elegans</i> via transcriptome and metabolome analysis. The results showed that CO significantly reduced fat accumulation in high-fat <i>C. elegans</i> by 10.34% (Oil Red O method) and 11.54% (TG content method), respectively. Furthermore, CO primarily altered the transcription levels of genes involved in longevity regulating pathway. Specifically, CO decreased lipid storage in high-fat <i>C. elegans</i> by inhibiting fat synthesis. In addition, CO supplementation modulated the abundance of metabolic biomarkers related to pyrimidine metabolism and riboflavin metabolism. The integrated transcriptome and metabolome analyses indicated that CO supplementation could alleviate fat accumulation in high-fat <i>C. elegans</i> by regulating retinol metabolism, drug metabolism-cytochrome P450, metabolism of xenobiotics by cytochrome P450, ascorbate and aldarate metabolism, and pentose and glucuronate interconversions. Overall, these findings highlight the potential health benefits of CO that could potentially be used as a functional edible oil.

Forrester S et al. (2007) Foodborne Pathog Dis "Evaluation of the pathogenicity of Listeria spp. in Caenorhabditis elegans."

Schwab U, Wiedmann M, Hoose WA, Milillo SR, Forrester S

[Foodborne Pathog Dis, 2007]

Caenorhabditis has proven to be a useful model for studying host-pathogen interactions as well as the ability of nematodes to serve as vectors for the dispersal of foodborne pathogens. In this study, we evaluated whether C. elegans can serve as a host for Listeria spp. While there was an effect of growth media on C. elegans killing, C. elegans exposed to L. monocytogenes and L. innocua pregrown in Luria-Bertani medium showed reduced survival when compared to nonpathogenic E. coli OP50, while L. seeligeri showed survival similar to E. coli OP50. In a preference assay, C. elegans preferred E. coli over L. monocytogenes and L. innocua, but showed no preference between L. monocytogenes and L. innocua. A gentamicin assay indicated that L. monocytogenes did not persist within the C. elegans intestinal tract. Our findings that L. monocytogenes and L. innocua strains tested have equally deleterious effects on C. elegans and that L. monocytogenes did not establish intestinal infection conflict with other recently published results, which found intestinal infection and killing of C. elegans by L. monocytogenes. Further studies are thus needed to clarify the interactions between L. monocytogenes and C. elegans, including effects of environmental conditions and strain differences on killing and intestinal infection.

Kaplan HS et al. (2018) Neuron "Sensorimotor Integration for Decision Making: How the Worm Steers."

Zimmer M, Kaplan HS

[Neuron, 2018]

Animals' movements actively shape their perception and subsequent decision making. In this issue of Neuron, Liu etal. (2018) show how C.elegans nematodes steer toward an odorant: a dedicated interneuron class integrates oscillatory olfactory signals, generated by head swings, with corollary discharge motor signals.

Abraham D et al. (1989) Am J Trop Med Hyg "Immunity to larval Brugia malayi in BALB/c mice: protective immunity and inhibition of larval development."

Grieve RB, Christensen BM, Abraham D, Holy JM

[Am J Trop Med Hyg, 1989]

The objective of this study was to analyze the immune response of mice to the larval stages of Brugia malayi. Male BALB/c mice were inoculated with 3 doses of irradiated third-stage larvae (L-3) of B. malayi and were subsequently challenged with L-3 implanted ip within diffusion chambers. After 3 weeks, larvae were recovered to determine their viability, length, and stage of development. A significant reduction in parasite survival was observed in immunized mice. Furthermore, larvae recovered from immunized mice were significantly shorter than larvae recovered from control mice. All larvae recovered from immunized mice were L-3, whereas 96% of larvae recovered from controls were fourth-stage larvae (L-4). Sera collected from control and immunized mice were tested for the presence of antibodies reactive with L-3 and L-4 antigens using an indirect fluorescent antibody assay employing frozen larval cross-sections as antigen. Sera recovered after challenge of control mice reacted with internal, but not surface, antigens of L-3 and L-4. Alternatively, sera from immunized mice reacted with both internal and external antigens of both L-3 and L-4.

Ali L et al. (2020) J Cell Biol "Mitochondrial translation, dynamics, and lysosomes combine to extend lifespan."

Ali L, Haynes CM

[J Cell Biol, 2020]

In this issue, Liu et al. (2019. J. Cell. Biol.https://doi.org/10.1083/jcb.201907067) find that the inhibition of mitochondrial ribosomes in combination with impaired mitochondrial fission or fusion increases C. elegans lifespan by activating the transcription factor HLH-30, which promotes lysosomal biogenesis.

Sese BT et al. (2009) J Toxicol Environ Health A "Toxicity of polycyclic aromatic hydrocarbons to the nematode Caenorhabditis elegans."

Reid BJ, Grant A, Sese BT

[J Toxicol Environ Health A, 2009]

The presence of polycyclic aromatic hydrocarbons (PAHs) in the environment has attracted much concern owing to their mutagenic and carcinogenic properties. Regulatory authorities have favored the use of biological indicators as an essential means of assessing potential toxicity of environmental pollutants. This study aimed to assess the toxicity of acenaphthene, phenanthrene, anthracene, fluoranthene, pyrene, and benzo[a]pyrene to Caenorhabditis elegans by measuring LC50 and EC50 values for growth and reproduction. The exposure to all chemicals was carried out in aqueous medium. All PAHs showed a low acute toxicity to C. elegans. There was no significant mortality in C. elegans after 24 h of exposure at PAH concentrations within (and indeed above) their respective solubility limits. Prolonged exposure (72 h) at high concentrations for acenaphthene (70,573 microg/L), phenanthrene (3758 microg/L), anthracene (1600 microg/L), fluoranthene (1955 microg/L), pyrene (1653 microg/L), and benzo[a]pyrene (80 microg/L) produced mortality. Results also showed that reproduction and growth were much more sensitive parameters of adverse response than lethality, and consequently may be more useful in assessing PAH toxicity using C. elegans. In comparison with previous studies, C. elegans was found to be approximately 2-fold less sensitive to acenaphthene, 5-fold less sensitive to phenanthrene, and 20-fold less sensitive to fluoranthene than Daphnia magna. However, the 48-h LC50 for benzo[a]pyrene (174 microg/L) reported in the present study with C. elegans was similar to that reported elsewhere for Daphnia magna (200 microg/L). Although C. elegans indicated greater sensitivity to benzo[a]pyrene than Artemia salina (174 microg/L vs. 10000 microg/L), the organism showed less sensitivity to pyrene (8 microg/L vs. 2418 microg/L), fluoranthene (40 microg/L vs. 2719 microg/L), and phenanthrene (677 microg/L vs. 4772 microg/L) than Artemia salina. Caenorhabditis elegans, while not the most sensitive of species for PAH toxicity assessment, may still hold applicability in screening of contaminated soils and sediments.