Biology subjects

Liu, W. J.

Publications and source records attributed to Liu, W. J..

5 recordsLinked to original sources

bioRxiv2026

Tau-induced ribosomal collisions impair memory through the activation of the integrated stress response

The formation of new long-term memories is reliant upon the spatial and temporal regulation of mRNA translation. Translational control has been demonstrated to be disrupted in neurodegenerative diseases, which exhibit impairments in both homeostatic translation and memory formation, such as Alzheimers disease (AD) and frontotemporal dementia (FTD). However, the precise mechanisms by which this dysregulation occurs, as well as the pathogenic consequences of this dysregulation have yet to be described. Here we establish that FTD-associated tau mutations impair protein synthesis prior to the onset of memory impairments by slowing ribosomal elongation speed, causing ribosomes to collide upon mRNAs. We reveal that this tau-induced ribosomal collision ultimately impairs memory-associated translation through activation of the integrated stress response (ISR) via GCN2. Pharmacological prevention of this ISR activation not only rescues memory formation in the PS19 mouse model of FTD, but also attenuates neuronal death, decreases tau phosphorylation and accumulation, and improves survival. Collectively, our data elucidates a novel mechanism by which mRNA translation is impaired early in neurodegeneration, identifies several pathological phenotypes which are traceable to impairments in mRNA translation, and highlights the therapeutic potential of rescuing these translational impairments.

neuroscience↗

bioRxiv2025

ZIKV NS5-mediated STAT2 degradation as a determinant of immune evasion and pathogenicity

Type I interferon (IFN) signaling is a central antiviral defense, with STAT2 driving the expression of IFN-stimulated genes (ISGs) to restrict viral infection. Many flaviviruses, including Zika virus (ZIKV), evade this pathway through non-structural protein 5 (NS5)-mediated ubiquitination and proteasomal degradation of STAT2, yet the contribution of this immune evasion strategy to viral fitness and pathogenesis remains incompletely defined. Here, using a multi-step mutational scanning strategy that jointly assessed STAT2 degradation and viral RNA replication, we identified a single NS5 residue, L162, as uniquely permissive to substitution that abolishes STAT2 degradation without compromising intrinsic replication functions. Substitution of L162 with alanine or glycine (L162A or L162G) selectively disrupted NS5 recruitment of the ZSWIM8-CUL3 E3 ubiquitin ligase, thereby preserving STAT2 stability and restoring IFN signaling. Recombinant ZIKV carrying these mutations exhibited reduced replication and enhanced ISG induction in human cells, defects fully rescued by STAT2 knockout. In A129 mice (type I IFN receptor deficient), mutant and WT viruses replicated comparably, but in human STAT2 knock-in mice, ZIKV-NS5L162G exhibited markedly reduced viral loads and disease. Notably, infection with ZIKV-NS5L162G elicited robust neutralizing antibody and T cell responses that conferred protection against WT challenge. Together, these findings establish NS5-mediated STAT2 degradation as a central determinant of ZIKV immune evasion, viral fitness and pathogenesis, and highlight disruption of NS5-STAT2 antagonism as a promising strategy for antiviral intervention and rational attenuation.

microbiology↗

bioRxiv2025

Microglia coordinate activity-dependent protein synthesis in neurons through metabolic coupling

De novo protein synthesis is required for long-lasting synaptic plasticity and memory, but it comes with a great metabolic cost. In the mammalian brain, it remains unclear which cell types and biological mechanisms are critical for sensing and responding to increased metabolic demand. Here we demonstrate that microglia, resident macrophages of the brain, coordinate metabolic coupling between endothelial cells, astrocytes, and neurons to fuel protein synthesis in active neurons. Increasing metabolic demand via a motor task stimulates microglia to secrete the hypoxia-responsive protein CYR61, increasing glucose transporter expression in brain vasculature. Depleting microglia reduces training-induced metabolic fluxes and neuronal protein synthesis, which can be reproduced by blocking CYR61 signaling. Thus, we define a neuroimmune metabolic circuit required for on-demand protein synthesis in mouse motor cortex.

neuroscience↗

bioRxiv2022

Minor differences in peptide presentation between chicken MHC class I molecules can explain differences in disease susceptibility

The highly polymorphic classical major histocompatibility complexes (MHCs) can confer resistance or susceptibility to diseases. The chicken MHC is known to confer decisive resistance or susceptibility to various economically-important pathogens, including the iconic oncogenic herpesvirus that causes Mareks disease (MD). Only one classical class I gene, BF2, is expressed at a high level in chickens, so it was relatively easy to discern a hierarchy from well-expressed thermostable fastidious specialist alleles to promiscuous generalist alleles that are less stable and expressed less on the cell surface. The BF2*1901 is more highly expressed and more thermostable than the closely-related BF2*1501, but the data for peptide repertoire available did not obviously correlate as expected. Here, we confirm for newly-developed chicken lines that the chicken haplotype B15 confers resistance to MD compared to B19. Using gas phase sequencing of peptide pools, and using immunopeptidomics involving mass spectroscopy, we find that the BF2*1901 binds a greater variety of amino acids in some anchor positions than BF2*1501. However, by X-ray crystallography, we find that the peptide-binding groove of BF2*1901 is narrower and shallower. Though the self-peptides bound to BF2*1901 may appear more various than those of BF2*1501, the structures show that the wider and deeper peptide-binding groove of BF2*1501 allows it to tightly accept many more peptides overall, correlating with the expected hierarchies for expression level, thermostability and MD resistance. Moreover, the 2 helix of BF2*1901 is higher than BF2*1501, potentially reducing the number of T cell clones that can recognize this fastidious class I molecule. IMPORTANCEDisease susceptibility mechanism is complicated, but chicken infection of Mareks disease (MD) is one of ideal models, considering the only one highly expressed classical MHC class I, BF2. The different susceptibility of the two close alleles BF2*1901 and BF2*1501 with minor difference of expression and thermostability is still unfathomed. Here, we confirm B15 chicken confers resistance to MD compared to B19. But the BF2*1901 binds a broader variety of anchoring peptides than BF2*1501. This mystery was solved by the structural determination of the two molecules with one similar peptide. The wider and deeper peptide-binding groove of BF2*1501 allows it to tightly accept many more peptides overall, which is concordant to the expected hierarchies for expression level, thermostability and MD resistance.

immunology↗

bioRxiv2021

Recombinant chimpanzee adenovirus AdC7 expressing dimeric tandem-repeat RBD of SARS-CoV-2 spike protein protects mice against COVID-19

A safe and effective vaccine is urgently needed to control the unprecedented COVID-19 pandemic. Four adenovirus vectored vaccines expressing spike (S) protein have advanced into phase 3 trials, with three approved for use. Here, we generated several recombinant chimpanzee adenovirus (AdC7) vaccines expressing S, receptor-binding domain (RBD) or dimeric tandem-repeat RBD (RBD-tr2). We found vaccination via either intramuscular or intranasal route was highly immunogenic in mice to elicit both humoral and cellular (Th1-based) immune responses. AdC7-RBD-tr2 showed higher antibody responses compared with both AdC7-S and AdC7-RBD. Intranasal administration of AdC7-RBD-tr2 additionally induced mucosal immunity with neutralizing activity in bronchoalveolar lavage fluid. Either single-dose or two-dose mucosal administration of AdC7-RBD-tr2 protected mice against SARS-CoV-2 challenge, with undetectable subgenomic RNA in lung and relieved lung injury. These results support AdC7-RBD-tr2 as a promising COVID-19 vaccine candidate.

immunology↗