Liu J et al. (2020) Elife "Turning away from danger."

Liu J, Scholz M

[Elife, 2020]

The flexible escape behavior exhibited by <i>C. elegans</i> in response to threats relies on a combination of feedback and feedforward circuits.

Liu J et al. (2024) Genetics "Adapting and optimizing GCaMP8f for use in Caenorhabditis elegans."

Scholz M, Bonnard E, Liu J

[Genetics, 2024]

Improved genetically-encoded calcium indicators (GECIs) are essential for capturing intracellular dynamics of both muscle and neurons. A novel set of GECIs with ultra-fast kinetics and high sensitivity was recently reported by Zhang et al. (Nature, 2023). While these indicators, called jGCaMP8, were demonstrated to work in Drosophila and mice, data for Caenorhabditis elegans were not reported. Here, we present an optimized construct for C. elegans and use this to generate several strains expressing GCaMP8f (fast variant of the indicator). Utilizing the myo-2 promoter, we compare pharyngeal muscle activity measured with GCaMP7f and GCaMP8f and find that GCaMP8f is brighter upon binding to calcium, shows faster kinetics and is not disruptive to the intrinsic contraction dynamics of the pharynx. Additionally, we validate its application for detecting neuronal activity in touch receptor neurons which reveals robust calcium transients even at small stimulus amplitudes. As such, we establish GCaMP8f as a potent tool for C. elegans research which is capable of extracting fast calcium dynamics at very low magnifications across multiple cell types.

Liu J et al. (2004) Proteins "Automatic target selection for structural genomics on eukaryotes."

Rost B, Montelione GT, Hegyi H, Liu J, Acton TB

[Proteins, 2004]

A central goal of structural genomics is to experimentally determine representative structures for all protein families. At least 14 structural genomics pilot projects are currently investigating the feasibility of high-throughput structure determination; the National Institutes of Health funded nine of these in the United States. Initiatives differ in the particular subset of "all families" on which they focus. At the NorthEast Structural Genomics consortium (NESG), we target eukaryotic protein domain families. The automatic target selection procedure has three aims: 1) identify all protein domain families from currently five entirely sequenced eukaryotic target organisms based on their sequence homology, 2) discard those families that can be modeled on the basis of structural information already present in the PDB, and 3) target representatives of the remaining families for structure determination. To guarantee that all members of one family share a common foldlike region, we had to begin by dissecting proteins into structural domain-like regions before clustering. Our hierarchical approach, CHOP, utilizing homology to PrISM, Pfam-A, and SWISS-PROT chopped the 103,796 eukaryotic proteins/ORFs into 247,222 fragments. Of these fragments, 122,999 appeared suitable targets that were grouped into &gt;27,000 singletons and &gt;18,000 multifragment clusters. Thus, our results suggested that it might be necessary to determine &gt;40,000 structures to minimally cover the subset of five eukaryotic proteomes.

Liu J et al. (1996) Science "Interaction between a putative mechanosensory membrane channel and a collagen."

Schrank B, Waterston RH, Liu J

[Science, 1996]

The degenerin family of proteins in Caenorhabditis elegans is homologous to subunits of the mammalian amiloride-sensitive epithelial sodium channels. Mutations in nematode degenerins cause cell death, probably because of defects in channel function. Genetic evidence was obtained that the unc-105 gene product represents a degenerin homolog affecting C. elegans muscles and that this putative channel interacts with type IV collagen in the extracellular matrix underlying the muscle cell. This interaction may serve as a mechanism of stretch-activated muscle contraction, and this system could provide a molecular model for the activation of mechanosensitive ion channels.AD - Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA.FAU - Liu, JAU - Liu JFAU - Schrank, BAU - Schrank BFAU - Waterston, R HAU - Waterston RHLA - engSI - GENBANK/J04694SI - GENBANK/M23704SI - GENBANK/M67507SI - GENBANK/U07224SI - GENBANK/U07888SI - GENBANK/U22327SI - GENBANK/X56979SI - GENBANK/X76730SI - GENBANK/Y00706ID - GM23883/GM/NIGMSPT - Journal ArticleCY - UNITED STATESTA - ScienceJID - 0404511RN - 0 (Helminth Proteins)RN - 0 (Sodium Channels)RN - 0 (Unc-105 protein)RN - 9007-34-5 (Collagen)SB - IMSB - S

Liu J et al. (2014) Oncogene "Insulin activates the insulin receptor to downregulate the PTEN tumour suppressor."

Lo S, Liu J, Chin-Sang I, Yu F, Yang X, Sun T, Chamberlain G, Visser-Grieve S, Yeung B, Lam A, Boudreau J, Papanicolaou T

[Oncogene, 2014]

Insulin and insulin-like growth factor-1 signaling have fundamental roles in energy metabolism, growth and development. Recent research suggests hyperactive insulin receptor (IR) and hyperinsulinemia are cancer risk factors. However, the mechanisms that account for the link between the hyperactive insulin signaling and cancer risk are not well understood. Here we show that an insulin-like signaling inhibits the DAF-18/(phosphatase and tensin homolog) PTEN tumour suppressor in Caenorhabditis elegans and that this regulation is conserved in human breast cancer cells. We show that inhibiting the IR increases PTEN protein levels, while increasing insulin signaling decreases PTEN protein levels. Our results show that the kinase region of IR subunit physically binds to PTEN and phosphorylates on Y27 and Y174. Our genetic results also show that DAF-2/IR negatively regulates DAF-18/PTEN during C. elegans axon guidance. As PTEN is an important tumour suppressor, our results therefore suggest a possible mechanism for increased cancer risk observed in hyperinsulinemia and hyperactive IR individuals.

Liu J et al. (2018) Genome Biol Evol "Developmental constraints on genome evolution in four bilaterian model species."

Robinson-Rechavi M, Liu J

[Genome Biol Evol, 2018]

Developmental constraints on genome evolution have been suggested to follow either an early conservation model or an &quot;hourglass&quot; model. Both models agree that late development strongly diverges between species, but debate on which developmental period is the most conserved. Here, based on a modified &quot;Transcriptome Age Index&quot; approach, i.e. weighting trait measures by expression level, we analyzed the constraints acting on three evolutionary traits of protein coding genes (strength of purifying selection on protein sequences, phyletic age, and duplicability) in four species: nematode worm Caenorhabditis elegans, fly Drosophila melanogaster, zebrafish Danio rerio, and mouse Mus musculus. In general, we found that both models can be supported by different genomic properties. Sequence evolution follows an hourglass model, but the evolution of phyletic age and of duplicability follow an early conservation model. Further analyses indicate that stronger purifying selection on sequences in the middle development are driven by temporal pleiotropy of these genes. In addition, we report evidence that expression in late development is enriched with retrogenes, which usually lack efficient regulatory elements. This implies that expression in late development could facilitate transcription of new genes, and provide opportunities for acquisition of function. Finally, in C. elegans, we suggest that dosage imbalance could be one of the main factors that cause depleted expression of high duplicability genes in early development.

Liu J et al. (2001) Cell "Defective interplay of activators and repressors with TFIH in xeroderma pigmentosum."

Wang XW, Chuikov S, Reinberg D, Liu J, Ge H, Conaway JW, Weber A, Libutti D, Akoulitchev S, Levens D, Harris CC, Conaway RC

[Cell, 2001]

Inherited mutations of the TFIIH helicase subunits xeroderma pigmentosum (XP) B or XPD yield overlapping DNA repair and transcription syndromes. The high risk of cancer in these patients is not fully explained by the repair defect. The transcription defect is subtle and has proven more difficult to evaluate. Here, XPB and XPD mutations are shown to block transcription activation by the FUSE Binding Protein (FBP), a regulator of c-myc expression, and repression by the FBP Interacting Repressor (FIR). Through TFIIH, FBP facilitates transcription until promoter escape, whereas after initiation, FIR uses TFIIH to delay promoter escape. Mutations in TFIIH that impair regulation by FBP and FIR affect proper regulation of c-myc expression and have implications in the development of malignancy.

Liu J et al. (2017) J Cell Biol "Ubiquitination of the PI3-kinase VPS-34 promotes VPS-34 stability and phagosome maturation."

Chen S, Liu J, Li M, Li L, Wang X

[J Cell Biol, 2017]

Apoptotic cells generated by programmed cell death are engulfed by phagocytes and enclosed within membrane-bound phagosomes. Maturation of apoptotic cell-containing phagosomes leads to formation of phagolysosomes where cell corpses are degraded. The class III phosphatidylinositol 3-kinase (PI3-kinase) VPS-34 coordinates with PIKI-1, a class II PI3-kinase, to produce PtdIns3P on phagosomes, thus promoting phagosome closure and maturation. Here, we identified UBC-13, an E2 ubiquitin-conjugating enzyme that functions in the same pathway with VPS-34 but in parallel to PIKI-1 to regulate PtdIns3P generation on phagosomes. Loss of ubc-13 affects early steps of phagosome maturation, causing accumulation of cell corpses. We found that UBC-13 functions with UEV-1, a noncatalytic E2 variant, and CHN-1, a U-box-containing E3 ubiquitin ligase, to catalyze K63-linked poly-ubiquitination on VPS-34 both in vitro and in Caenorhabditis elegans Loss of ubc-13, uev-1, or chn-1 disrupts ubiquitin modification of VPS-34 and causes significantly reduced VPS-34 protein levels. Our data suggest that K63-linked ubiquitin modification serves as a general mechanism to modulate VPS-34 stability in multiple processes.

Liu J et al. (2008) Dev Cell "The C. elegans SYS-1 protein is a bona fide beta-catenin."

Kimble J, Liu J, Amaya MF, Phillips BT, Xu W

[Dev Cell, 2008]

C. elegans SYS-1 has key functional characteristics of a canonical beta-catenin, but no significant sequence similarity. Here, we report the SYS-1 crystal structure, both on its own and in a complex with POP-1, the C. elegans TCF homolog. The two structures possess signature features of canonical beta-catenin and the beta-catenin/TCF complex that could not be predicted by sequence. Most importantly, SYS-1 bears 12 armadillo repeats and the SYS-1/POP-1 interface is anchored by a conserved salt-bridge, the "charged button." We also modeled structures for three other C. elegans beta-catenins to predict the molecular basis of their distinct binding properties. Finally, we generated a phylogenetic tree, using the region of highest structural similarity between SYS-1 and beta-catenin, and found that SYS-1 clusters robustly within the beta-catenin clade. We conclude that the SYS-1 protein belongs to the beta-catenin family and suggest that additional divergent beta-catenins await discovery.

Liu J et al. (2018) Prev Nutr Food Sci "Epigallocatechin-3-Gallate Reduces Fat Accumulation in Caenorhabditis elegans."

Liu J, Peng Y, Park Y, Yue Y, Shen P

[Prev Nutr Food Sci, 2018]

Epigallocatechin gallate (EGCG) is a polyphenol that is abundant in green tea. It has been reported that consumption of EGCG can contribute to weight loss, however, the underlying mechanism is not fully understood. To determine how EGCG reduces body fat, an organism model <i>Caenorhabditis elegans</i> was used, which is a useful animal model system in exploring crucial biological mechanisms that are readily applicable to humans. In this study, different strains were raised for two days on <i>Escherichia coli</i> OP 50 diet with or without 100 M and 200 M EGCG treatment. The current results showed that 100 M and 200 M EGCG significantly reduced the triglyceride content of wild type worms by 10% and 20% (<i>P</i>-value&lt;0.01 and &lt;0.001, respectively) compared to the control, respectively, without affecting its food intake and physiological behaviors. Additionally, EGCG could effectively reduce fat accumulation in <i>C. elegans</i> dependent on <i>atgl-1</i> (encoding a homolog of adipose triglyceride lipase), which suggests that EGCG controls the body fat by inhibiting adipogenesis.