Biology subjects

Guo, S.-K.

Publications and source records attributed to Guo, S.-K..

6 recordsLinked to original sources

bioRxiv2026

Evasion of Hepatic ILC1 Immunosurveillance Drives Breast Cancer Liver Metastasis

Metastasis, the dissemination of cancer cells to distant organs, is an inefficient process1, yet remains the leading cause of cancer-related mortality2. The cellular barriers and evasion mechanisms governing organ-specific susceptibility remain incompletely understood3-5, hindering the development of effective anti-metastatic therapies6. Here, we show that liver-resident type 1 innate lymphoid cells (ILC1s) constitute an essential immunosurveillance barrier against breast cancer liver metastasis that can be bypassed through either cancer cell intrinsic or host-dependent mechanisms. In a multi-organ metastatic breast cancer patient cohort, liver metastasis occurred later and was associated with poorer survival than lung metastasis, with elevated body mass index emerging as a clinical risk factor. This metabolic vulnerability was recapitulated in mice, where a high-fat diet induced hepatosteatosis and selectively enhanced breast cancer colonization of the liver. Mechanistically, liver and lung colonization were restrained by ILC1s and circulating natural killer (NK) cells, respectively. Following cancer cell challenge, NK cells expanded and activated, employing lytic granule pathways and the death receptor DR5 for clearance, whereas activated ILC1s selectively required high DR5 expression on cancer cells, supported by AP-2a (TFAP2A) mediated transcriptional activation, for effective immunosurveillance. Heterozygous copy number deletion at TNFRSF10B (encoding DR5) in human tumours reduced DR5 expression and predisposed to liver metastasis. Hepatosteatosis further compromised this barrier by reducing IL-15 expression in macrophages, thereby depleting hepatic ILC1s effects reversible with glucagon-like peptide-1 (GLP-1) receptor agonists. Thus, hepatic ILC1s form a critical organ-specific barrier to breast cancer metastasis, vulnerable to both cancer cell-intrinsic DR5 downregulation and host metabolic dysfunction.

immunology↗

bioRxiv2024

Multi-dimensionality of tree communities structure host-parasitoid networks and their phylogenetic composition

Environmental factors can influence ecological networks, but these effects are poorly understood in the realm of the phylogeny of host-parasitoid interactions. Especially, we lack a comprehensive understanding of the ways that biotic factors, including plant species richness, overall community phylogenetic and functional composition of consumers, and abiotic factors such as microclimate, determining host-parasitoid network structure and host-parasitoid community dynamics. To address this, we leveraged a five-year dataset of trap-nesting bees and wasps and their parasitoids collected in a highly-controlled, large-scale subtropical tree biodiversity experiment. We tested for effects of tree species richness, tree phylogenetic and functional diversity, and species and phylogenetic composition on species and phylogenetic diversity of both host and parasitoid communities and the composition of their interaction networks. We show that multiple components of tree diversity and canopy cover impacted both, species and phylogenetic composition of hosts and parasitoids. Generally, phylogenetic associations between hosts and parasitoids reflected non-randomly structured interactions between phylogenetic trees of hosts and parasitoids. Further, host-parasitoid network structure was influenced by tree species richness, tree phylogenetic diversity, and canopy cover. Our study indicates that the composition of higher trophic levels and corresponding interaction networks are determined by plant diversity and canopy cover especially via trophic links in species-rich ecosystems.

ecology↗

bioRxiv2023

Temporal control by co-factors prevents kinetic trapping in retroviral Gag lattice assembly

For retroviruses like HIV to proliferate, they must form virions shaped by the self-assembly of Gag polyproteins into a rigid lattice. This immature Gag lattice has been structurally characterized and reconstituted in vitro, revealing the sensitivity of lattice assembly to multiple co-factors. Due to this sensitivity, the energetic criterion for forming stable lattices is unknown, as are their corresponding rates. Here, we use a reaction-diffusion model designed from the cryo-ET structure of the immature Gag lattice to map a phase diagram of assembly outcomes controlled by experimentally constrained rates and free energies, over experimentally relevant timescales. We find that productive assembly of complete lattices in bulk solution is extraordinarily difficult due to the large size of this [~]3700 monomer complex. Multiple Gag lattices nucleate before growth can complete, resulting in loss of free monomers and frequent kinetic trapping. We therefore derive a time-dependent protocol to titrate or activate the Gag monomers slowly within the solution volume, mimicking the biological roles of co-factors. This general strategy works remarkably well, yielding productive growth of self-assembled lattices for multiple interaction strengths and binding rates. By comparing to the in vitro assembly kinetics, we can estimate bounds on rates of Gag binding to Gag and the cellular co-factor IP6. Our results show that Gag binding to IP6 can provide the additional time-delay necessary to support smooth growth of the immature lattice with relatively fast assembly kinetics, mostly avoiding kinetic traps. Our work provides a foundation for predicting and disrupting formation of the immature Gag lattice via targeting specific protein- protein binding interactions.

biophysics↗

bioRxiv2022

Defects in the HIV immature lattice support essential lattice remodeling within budded virions

For HIV virions to become infectious, the immature lattice of Gag polyproteins attached to the virion membrane must be cleaved. Cleavage cannot initiate without the protease formed by the homo-dimerization of domains linked to Gag. However, only 5% of the Gag polyproteins, termed Gag-Pol, carry this protease domain, and they are embedded within the structured lattice. The mechanism of Gag-Pol dimerization is unknown. Here, we use reaction-diffusion simulations of the immature Gag lattice as derived from experimental structures, showing that dynamics of the lattice on the membrane is unavoidable due to the missing 1/3 of the spherical protein coat. These dynamics allow for Gag-Pol molecules carrying the protease domains to detach and reattach at new places within the lattice. Surprisingly, dimerization timescales of minutes or less are achievable for realistic binding energies and rates despite retaining most of the large-scale lattice structure. We derive a formula allowing extrapolation of timescales as a function of interaction free energy and binding rate, thus predicting how additional stabilization of the lattice would impact dimerization times. We further show that during assembly, dimerization of Gag-Pol occurs stochastically and therefore must be actively suppressed to prevent early activation. By direct comparison to recent biochemical measurements within budded virions, we find that only moderately stable hexamer contacts (-12kBT<{Delta}G<-8kBT) retain both the dynamics and lattice structures that are consistent with experiment. These dynamics are likely essential for proper maturation, and our models quantify and predict lattice dynamics and protease dimerization timescales that define a key step in understanding formation of infectious viruses. Statement of SignificanceFor retroviruses such as HIV-1, the Gag polyprotein assembles an immature lattice that ensures successful budding from the cell plasma membrane. The first step in the subsequent maturation requires a pair of protease domains embedded within the lattice to form a homodimer. We show here that this homo-dimerization can proceed within minutes despite involving a small subset of Gag monomers, due to the incompleteness of the immature lattice. Using reaction-diffusion simulations, we quantify timescales of first dimerization events between the protease domains and define a formula to extrapolate across a range of energies and rates. Our models illustrate how protein contacts can be weakened to disrupt lattice assembly or stabilized to slow the remodeling essential for viral infectivity.

biophysics↗

bioRxiv2021

Nascent clathrin lattices spontaneously disassemble without sufficient adaptor proteins

Clathrin-coated structures must assemble on cell membranes to perform their primary function of receptor internalization. These structures show marked plasticity and instability, but what conditions are necessary to stabilize against disassembly have not been quantified. Recent in vitro fluorescence experiments have measured kinetics of stable clathrin assembly on membranes as controlled by key adaptor proteins like AP-2. Here, we combine this experimental data with microscopic reaction-diffusion simulations and theory to quantify mechanisms of stable vs unstable clathrin assembly on membranes. Both adaptor binding and dimensional reduction on the 2D surface are necessary to reproduce the cooperative kinetics of assembly. By applying our model to more physiologic-like conditions, where the stoichiometry and volume to area ratio are significantly lower than in vitro, we show that the critical nucleus contains ~25 clathrin, remarkably similar to sizes of abortive structures observed in vivo. Stable nucleation requires a stoichiometry of adaptor to clathrin that exceeds 1:1, meaning that AP-2 on its own has too few copies to nucleate lattices. Increasing adaptor concentration increases lattice sizes and nucleation speeds. For curved clathrin cages, we quantify both the cost of bending the membrane and the stabilization required to nucleate cages in solution. We find the energetics are comparable, suggesting that curving the lattice could offset the bending energy cost. Our model predicts how adaptor density controls stabilization of clathrin-coated structures against spontaneous disassembly, and shows remodeling and disassembly does not require ATPases, which is a critical advance towards predicting control of productive vesicle formation. Significance StatementStochastic self-assembly of clathrin-coated structures on the plasma membrane is essential for transport into cells. We show here that even with abundant clathrin available, robust nucleation and growth into stable structures on membranes is not possible without sufficient adaptor proteins. Our results thus provide quantitative justification for why structures observed to form in vivo can still spontaneously disassemble over many seconds. The ATPases that drive clathrin disassembly after productive vesicle formation are therefore not necessary to control remodeling during growth. With parameterization against in vitro kinetics of assembly on membranes, our reaction-diffusion model provides a powerful and extensible tool for establishing determinants of productive assembly in cells.

biophysics↗

bioRxiv2020

The oriental fruit moth genome provides insights into evolutionary adaptation of tortricid pests

Moths of the family Tortricidae (Insecta: Lepidoptera) usually distribute in temperate and tropical high upland regions. The oriental fruit moth (OFM) Grapholita molesta is a globally important pest of stone and pome fruit from this family. In this study, we assembled a chromosome-level genome for the OFM and conducted a comparative genomic analysis with other lepidopterans. This genome was assembled to 28 chromosomes with a size of 517.71 Mb, an N50 of 19.5 Mb, and a BUSCO completeness of 97.1%. In total, 19968 protein-coding genes were predicted, among which 15269 were functionally annotated. We manually annotated ten gene families for 13 representative genomes from the Lepidopteran. In general, two tortricid moths have a moderate number of detoxification and receptor genes and the lowest number of HSP genes, congruent with their polyphagous dietary and pattern of distribution. However, the OFM has the highest number of P450, I Rs and ORs among all species. Compared to the other tortricid species of the codling moth Cydia pomonella, the OFM has more genes in all gene families. Our results indicate that the high number of some detoxification and receptor genes may be related to the strong adaptation of OFM as a global pest. The high-quality genome of OFM provides an invaluable resource for understanding the ecology, genetics, and evolution of tortricid moths.

genomics↗