Professional Education


  • Doctor of Philosophy, University of California Davis (2018)

Stanford Advisors


All Publications


  • TMEM41B and VMP1 modulate cellular lipid and energy metabolism for facilitating dengue virus infection. PLoS pathogens Yousefi, M., Lee, W. S., Yan, B., Cui, L., Yong, C. L., Yap, X., Tay, K. S., Qiao, W., Tan, D., Nurazmi, N. I., Linster, M., Smith, G. J., Lee, Y. H., Carette, J. E., Ooi, E. E., Chan, K. R., Ooi, Y. S. 2022; 18 (8): e1010763

    Abstract

    Transmembrane Protein 41B (TMEM41B) and Vacuole Membrane Protein 1 (VMP1) are two ER-associated lipid scramblases that play a role in autophagosome formation and cellular lipid metabolism. TMEM41B is also a recently validated host factor required by flaviviruses and coronaviruses. However, the exact underlying mechanism of TMEM41B in promoting viral infections remains an open question. Here, we validated that both TMEM41B and VMP1 are essential host dependency factors for all four serotypes of dengue virus (DENV) and human coronavirus OC43 (HCoV-OC43), but not chikungunya virus (CHIKV). While HCoV-OC43 failed to replicate entirely in both TMEM41B- and VMP1-deficient cells, we detected diminished levels of DENV infections in these cell lines, which were accompanied by upregulation of the innate immune dsRNA sensors, RIG-I and MDA5. Nonetheless, this upregulation did not correspondingly induce the downstream effector TBK1 activation and Interferon-beta expression. Despite low levels of DENV replication, classical DENV replication organelles were undetectable in the infected TMEM41B-deficient cells, suggesting that the upregulation of the dsRNA sensors is likely a consequence of aberrant viral replication rather than a causal factor for reduced DENV infection. Intriguingly, we uncovered that the inhibitory effect of TMEM41B deficiency on DENV replication, but not HCoV-OC43, can be partially reversed using exogenous fatty acid supplements. In contrast, VMP1 deficiency cannot be rescued using the metabolite treatment. In line with the observed phenotypes, we found that both TMEM41B- and VMP1-deficient cells harbor higher levels of compromised mitochondria, especially in VMP1 deficiency which results in severe dysregulations of mitochondrial beta-oxidation. Using a metabolomic profiling approach, we revealed distinctive global dysregulations of the cellular metabolome, particularly lipidome, in TMEM41B- and VMP1-deficient cells. Our findings highlight a central role for TMEM41B and VMP1 in modulating multiple cellular pathways, including lipid mobilization, mitochondrial beta-oxidation, and global metabolic regulations, to facilitate the replication of flaviviruses and coronaviruses.

    View details for DOI 10.1371/journal.ppat.1010763

    View details for PubMedID 35939522

  • Flock house virus as a vehicle for aphid Virus-induced gene silencing and a model for aphid biocontrol approaches JOURNAL OF PEST SCIENCE Jiang, J., Erickson, A., Qiao, W., Matsumura, E. E., Falk, B. W. 2022
  • A memory of eS25 loss drives resistance phenotypes. Nucleic acids research Johnson, A. G., Flynn, R. A., Lapointe, C. P., Ooi, Y. S., Zhao, M. L., Richards, C. M., Qiao, W. n., Yamada, S. B., Couthouis, J. n., Gitler, A. D., Carette, J. E., Puglisi, J. D. 2020

    Abstract

    In order to maintain cellular protein homeostasis, ribosomes are safeguarded against dysregulation by myriad processes. Remarkably, many cell types can withstand genetic lesions of certain ribosomal protein genes, some of which are linked to diverse cellular phenotypes and human disease. Yet the direct and indirect consequences from these lesions are poorly understood. To address this knowledge gap, we studied in vitro and cellular consequences that follow genetic knockout of the ribosomal proteins RPS25 or RACK1 in a human cell line, as both proteins are implicated in direct translational control. Prompted by the unexpected detection of an off-target ribosome alteration in the RPS25 knockout, we closely interrogated cellular phenotypes. We found that multiple RPS25 knockout clones display viral- and toxin-resistance phenotypes that cannot be rescued by functional cDNA expression, suggesting that RPS25 loss elicits a cell state transition. We characterized this state and found that it underlies pleiotropic phenotypes and has a common rewiring of gene expression. Rescuing RPS25 expression by genomic locus repair failed to correct for the phenotypic and expression hysteresis. Our findings illustrate how the elasticity of cells to a ribosome perturbation can drive specific phenotypic outcomes that are indirectly linked to translation and suggests caution in the interpretation of ribosomal protein gene mutation data.

    View details for DOI 10.1093/nar/gkaa444

    View details for PubMedID 32463448

  • Enhancing the Antiviral Efficacy of RNA-Dependent RNA Polymerase Inhibition by Combination with Modulators of Pyrimidine Metabolism. Cell chemical biology Liu, Q. n., Gupta, A. n., Okesli-Armlovich, A. n., Qiao, W. n., Fischer, C. R., Smith, M. n., Carette, J. E., Bassik, M. C., Khosla, C. n. 2020

    Abstract

    Genome-wide analysis of the mode of action of GSK983, a potent antiviral agent, led to the identification of dihydroorotate dehydrogenase as its targetĀ along with the discovery that genetic knockdown of pyrimidine salvage sensitized cells to GSK983. Because GSK983 is an ineffective antiviral in the presence of physiological uridine concentrations, we explored combining GSK983 with pyrimidine salvage inhibitors. We synthesized and evaluated analogs of cyclopentenyl uracil (CPU), an inhibitor of uridine salvage. We found that CPU was converted into its triphosphate in cells. When combined with GSK983, CPU resulted in large drops in cellular UTP and CTP pools. Consequently, CPU-GSK983 suppressed dengue virus replication in the presence of physiological concentrations of uridine. In addition, the CPU-GSK983 combination markedly enhanced the effect of RNA-dependent RNA polymerase (RdRp) inhibition on viral infection. Our findings highlight a new host-targeting strategy for potentiating the antiviral activity of RdRp inhibitors.

    View details for DOI 10.1016/j.chembiol.2020.05.002

    View details for PubMedID 32442424

    View details for PubMedCentralID PMC7241336