Biology subjects

Wong, S.-S.

Publications and source records attributed to Wong, S.-S..

6 recordsLinked to original sources

bioRxiv2024

Centrioles generate two scaffolds with distinct biophysical properties to build mitotic centrosomes

Mitotic centrosomes form when centrioles recruit large amounts of pericentriolar material (PCM) around themselves. The PCM comprises hundreds of proteins, yet it can assemble and disassemble within minutes, leading to much debate about its physical nature. Here we show that Drosophila Spd-2 fluxes out from centrioles, recruiting Polo and Aurora A to catalyse the assembly of a solid-like Cnn-scaffold and a more liquid-like TACC-scaffold, respectively. Both scaffolds can assemble and recruit PCM proteins independently, but both are required for proper centrosome assembly, with the Cnn-scaffold providing mechanical strength, and the TACC-scaffold locally concentrating centriole and centrosome proteins. Recruiting Spd-2, but not Cnn or TACC, to the surface of synthetic beads injected into early embryos reconstitutes several aspects of mitotic centrosome assembly on the bead surface, and this depends on the ability of Spd-2 to recruit Polo and AurA. Thus, Spd-2 molecules flux out from the centriole recruiting Polo and AurA to promote the assembly of two scaffolds with distinct properties to support mitotic centrosome assembly in flies.

cell biology↗

bioRxiv2024

A hemagglutinin and neuraminidase biased immunological memory shapes the dynamics of antibody responses to Influenza A virus

Influenza A virus (IAV) infection establishes a more diverse immunological memory to different viral proteins compared to vaccination. We hypothesized that the relative abundance of pre-existing immune memory to different viral antigens could skew post-infection antibody responses. To explore this, we generated mouse models with either an IAV hemagglutinin (HA)- or neuraminidase (NA)-biased immunological memory. We inoculated groups of mice with cocktails of isogenic viruses bearing antigenically-distinct HA (H3v) or NA (N2v) chosen to span the IAV H3N2 human circulation history. We challenged the mice with two H3N2 strains of opposing virulence and antigenic distance (AD) and examined the post-infection antibody landscapes. In both challenges, immune-naive mice seroconverted to both HA and NA whereas in primed mice, antibody response was detected to the antigen for which there is no pre-existing memory. In cases where the homologous antibody response was blunted, there was diversification on the breadth of response to antigenically-related strains with low baseline titers. Our findings clarifies the concept of "original antigenic sin" and demonstrate a mechanism by which the dynamics of antibody responses to HA and NA after infection can be altered by pre-existing immunity.

immunology↗

bioRxiv2023

Cdk/Cyclin activity helps set mitotic centrosome size by influencing the centrosome growth rate and growth period

Mitotic centrosomes assemble when centrioles recruit large amounts of pericentriolar material (PCM) around themselves in preparation for cell division. How the mitotic PCM grows to the correct size is unclear. In Drosophila syncytial embryos, thousands of mitotic centrosomes assemble in a common cytoplasm as the embryo proceeds through 13 rounds of near-synchronous nuclear division. During nuclear cycles (NCs) 11-13 these divisions gradually slow, and we find that mitotic centrosomes respond by reciprocally slowing their growth rate and increasing their growth period so that they grow to a consistent size at each cycle. This size homeostasis is enforced, at least in part, by the Cdk/Cyclin cell cycle oscillator (CCO). Moderate levels of CCO activity appear to initially promote centrosome growth by stimulating Polo/PLK1 recruitment to centrosomes, while higher levels of activity subsequently inhibit centrosome growth by phosphorylating centrosome proteins to decrease their centrosomal recruitment and/or maintenance as the embryos enter mitosis. Thus, the CCO initially promotes, and subsequently restricts, mitotic centrosome growth to help ensure that centrosomes grow to a consistent size.

cell biology↗

bioRxiv2022

The episodic resurgence of highly pathogenic avian influenza H5 virus

Highly pathogenic avian influenza (HPAI) H5N1 activity has intensified globally since 2021, replacing the dominant clade 2.3.4.4 H5N8 virus. H5N1 viruses have spread rapidly to four continents, causing increasing reports of mass mortality in wild birds and poultry. The ecological and virological properties required for future mitigation strategies are unclear. Using epidemiological, spatial and genomic approaches, we demonstrate changes in the source of resurgent H5 HPAI and reveal significant shifts in virus ecology and evolution. Outbreak data indicates key resurgent events in 2016/17 and 2020/21 that contributed to the panzootic spread of H5N1 in 2021/22, including an increase in virus diffusion velocity and persistence in wild birds. Genomic analysis reveals that the 2016/17 epizootics originated in Asia, where HPAI H5 reservoirs are documented as persistent. However, in 2020/21, 2.3.4.4b H5N8 viruses emerged in domestic poultry in Africa, featuring several novel mutations altering the HA structure, receptor binding, and antigenicity. The new H5N1 virus emerged from H5N8 through reassortment in wild birds along the Adriatic flyway around the Mediterranean Sea. It was characterized by extensive reassortment with low pathogenic avian influenza in domestic and wild birds as it spread globally. In contrast, earlier outbreaks of H5N8 were caused by a more stable genetic constellation, highlighting dynamic changes in HPAI H5 genomic evolution. These results suggest a shift in the epicenter of HPAI H5 beyond Asia to new regions in Africa, the Middle East, Europe, and North and South America. The persistence of HPAI H5 with resurgence potential in domestic birds indicates that elimination strategies remain a high priority.

microbiology↗

bioRxiv2022

Centriole growth is not limited by a finite pool of components, but is limited by the Cdk1/Cyclin-dependent phosphorylation of Ana2/STIL

Centrioles duplicate once per cell cycle but it is unclear how daughter centrioles assemble at the right time and place and grow to the right size. Here we show that in early Drosophila embryos the cytoplasmic concentrations of the key centriole assembly proteins Asl, Plk4, Ana2, Sas-6 and Sas-4 are low, but remain constant throughout the assembly process-- indicating that none of them are limiting for centriole assembly. The cytoplasmic diffusion rate of Ana2/STIL, however, increased significantly towards the end of S-phase as Cdk/Cyclin activity in the embryo increased. A mutant form of Ana2 that cannot be phosphorylated by Cdk/Cyclins did not exhibit the diffusion rate change, and allowed daughter centrioles to grow for an extended period. Thus, the Cdk/Cyclin-dependent phosphorylation of cytoplasmic Ana2 seems to reduce the efficiency of daughter centriole assembly towards the end of S-phase. This helps to ensure that daughter centrioles stop growing at the correct time, and presumably also helps to explain why centrioles cannot duplicate during mitosis when Cdk/Cyclin activity is high.

cell biology↗

bioRxiv2021

Mother centrioles generate a local pulse of Polo/PLK1 activity to initiate mitotic centrosome assembly

Mitotic centrosomes are formed when centrioles start to recruit large amounts of pericentriolar material (PCM) around themselves in preparation for mitosis. This centrosome "maturation" requires the centrioles and also Polo/PLK1 protein kinase. The PCM comprises several hundred proteins and, in Drosophila, Polo cooperates with the conserved centrosome proteins Spd-2/CEP192 and Cnn/CDK5RAP2 to assemble a PCM scaffold around the mother centriole that then recruits other PCM client proteins. We show here that in Drosophila syncytial blastoderm embryos, centrosomal Polo levels rise and fall during the assembly process--peaking, and then starting to decline, even as levels of the PCM scaffold continue to rise and plateau. Experiments and mathematical modelling indicate that a centriolar pulse of Polo activity, potentially generated by the interaction between Polo and its centriole receptor Ana1 (CEP295 in humans), could explain these unexpected scaffold assembly dynamics. We propose that centrioles generate a local pulse of Polo activity prior to mitotic entry to initiate centrosome maturation, explaining why centrioles and Polo/PLK1 are normally essential for this process.

cell biology↗