Biology subjects

Wang, J.-Z.

Publications and source records attributed to Wang, J.-Z..

6 recordsLinked to original sources

bioRxiv2026

Drug Functional Site-Unknown Molecular Targets Exemplified by SARS-CoV-2 pseudoknot and ribosomal frameshifting-modulators

The -1 Programmed Ribosomal Frameshifting (-1 PRF) signal of SARS-CoV-2, driven by a conserved three-stemmed RNA pseudoknot (PK), is indispensable for viral replication and represents a structurally stable yet underexplored therapeutic target. Unlike rapidly mutating viral proteins, this RNA element offers an opportunity for durable intervention but has historically been considered "undruggable". We developed an integrative drug discovery and characterization pipeline that combines molecular docking, molecular dynamics simulations, and dual-luciferase assays to systematically identify and validate frameshifting-efficiency (Feff) modulators from FDA-approved compounds. To move beyond traditional similarity-based screening, we introduced a contact-distribution-matching method, which ranks candidate compounds by comparing their predicted RNA interaction fingerprints with those of reference modulators. This computational approach, paired with experimental validation, enabled us to expand the repertoire of Feff modulators and establish correlations between binding patterns and functional outcomes. To uncover the underlying mechanisms, we applied steered molecular dynamics simulations and single-molecule optical tweezers measurements, revealing that Feff-enhancing modulators preferentially stabilize the remote stem (stem 3) of the PK, promoting variety of intermediate force species with the beginning base pairs of stem 1 being refolded, even after those base pairs have been unwound by ribosome. The refold of the tips of the stem 1 in turn "push back" the ribosome on the slippery sequence to result in enhanced frameshifting. On the other hand, Feff-suppressing modulators rigidify early stem regions, increasing resistance to ribosomal progression and increase the drop-off rate, eventually leading to a reduced -1 frame to 0 frame ratio in translation. Together, these findings provide the first integrated demonstration of how small molecules can modulate -1 PRF by altering RNA PK folding dynamics. More broadly, our framework establishes a generalizable strategy for rationally targeting structured RNAs with repurposed drugs and offers new opportunities to expand the druggable genome to include noncoding RNA elements and other biomolecular targets lacking known functional sites.

biochemistry↗

bioRxiv2025

Longitudinal and large-scale monitoring of transcriptome and RBP-RNA interactome in living cells by engineered protein nanocages

Nondestructive sequencing of RNA from live cells is essential for monitoring and understanding dynamic biological processes. However, most existing RNA sequencing methods rely on cell lysis or fixation, limiting their applicability for longitudinal studies. Here, we introduce POND-seq (Protein nanocage-empOwered Non-Destructive sequencing), a novel approach that employs secretory protein nanocages fused with RNA-binding proteins (RBPs) to capture the RBP-RNA interactome and transcriptome in live cells. POND-seq reliably identifies RNA targets of canonical RBPs across multiple cell types. By fusing poly(A)-binding protein (PABPC1) to the nanocage, we demonstrate that POND-seq can monitor transcriptomic changes in response to signaling stimuli and selectively capture cell-type-specific transcriptomes from mixed populations. Additionally, POND-seq facilitates the dissection of RNA-binding domains and key amino acid residues critical for RBP-RNA interactions. We further highlight its utility in large-scale screening, offering compelling evidence for the pathogenicity of FMR1 variants. POND-seq represents a transformative advancement in RNA biology, cell biology and precision medicine, enabling unprecedented insights into cellular dynamics and disease mechanisms.

molecular biology↗

bioRxiv2021

Reciprocity between retrograde signal and putative metalloprotease reconfigures plastidial metabolism and structure

Reconfiguration of the plastidial proteome in response to environmental inputs is central to readjustment of its metabolic and structural states. This is necessary for the functionality of this metabolic hub, and the maintenance of organismal integrity. This report establishes the role of the plastidial retrograde signaling metabolite, MEcPP, in increasing the abundance of the putative plastidial metalloprotease (VIR3), and the ensuing decline of VIR3 target enzymes, ascorbate peroxidase and glyceraldehyde 3-phophate dehydrogenase B. The decreased abundance of these enzymes is linked to increased levels of their substrates: H2O2, an elicitor of salicylic acid production and stromule formation; and G3P the substrate for MEcPP synthesis. High-light treatment of wild type plants recapitulated the VIR3-associated reconfiguration of the plastidial metabolic and structural states. These results identify a previously unrecognized link between the stress-induced plastidial retrograde signaling metabolite and a putative zinc-binding metalloprotease. Moreover, the data reveal that the reciprocity between these two components, results in the reconfiguration of the metabolic and structural states of the plastid, deemed necessary to maintain cellular integrity and to shape adaptive responses.

plant biology↗

bioRxiv2021

A plastidial retrograde-signal potentiates biosynthesis of systemic stress response activators

O_LIPlants employ an array of intricate and hierarchical signaling cascades to perceive and transduce informational cues to synchronize and tailor adaptive responses. Systemic stress response (SSR) is a recognized complex signaling and response network quintessential to plants local and distal responses to environmental triggers, however, the identity of the initiating signals has remained fragmented. C_LIO_LIHere, we show that both biotic (aphids and viral pathogens) and abiotic (high-light and wounding) stresses induce accumulation of the plastidial-retrograde-signaling metabolite, methylerythritol cyclodiphosphate (MEcPP), leading to reduction of the phytohormone, auxin, and the subsequent decreased expression of the phosphatase, PP2C.D1. C_LIO_LIThis enables phosphorylation of mitogen-activated protein kinases (MAPK3/6), and the consequential induction of the downstream events ultimately resulting in biosynthesis of the two SSR priming metabolites, pipecolic- and N-hydroxy-pipecolic acid. C_LIO_LIThis work identifies plastids as the initiation site, and the plastidial retrograde-signal, MEcPP as the initiator of a multi-component signaling cascade potentiating the biosynthesis of SSR activators, in response to biotic and abiotic triggers. C_LI

plant biology↗

bioRxiv2021

Atmospheric particulate matter aggravates CNS demyelination via TLR-4/NF-κB-mediated microglia pathogenic activities

Atmospheric Particulate Matter (PM) is one of the leading environmental risk factors for the global burden of disease. Increasing epidemiological studies demonstrated that PM plays a significant role in CNS demyelinating disorders; however, there is no direct testimony of this, and yet the molecular mechanism by which the occurrence remains unclear. Using multiple in vivo and in vitro strategies, in the present study we demonstrate that PM exposure aggravates neuroinflammation, myelin injury, and dysfunction of movement coordination ability via boosting microglial pro-inflammatory activities, in both the pathological demyelination and physiological myelinogenesis animal models. Indeed, pharmacological disturbance combined with RNA-seq and ChIP-seq suggests that TLR-4/NF-{kappa}B signaling mediated a core network of genes that control PM-triggered microglia pathogenicity. In summary, our study defines a novel atmospheric environmental mechanism that mediates PM-aggravated microglia pathogenic activities, and establishes a systematic approach for the investigation of the effects of environmental exposure in neurologic disorders. SignificanceAn atmospheric trigger, the respirable particulate matter boost microglia pathogenic activities in the context of CNS demyelination by activating TLR-4/NF-{kappa}B signaling axis in animal models of immune- and toxicity-induced demyelination, as well as myelinogenesis during postnatal development.

neuroscience↗

bioRxiv2018

Tau accumulation activates STAT1 triggering memory deficits via suppressing NMDA receptor expression

Intracellular tau accumulation forming neurofibrillary tangles is hallmark pathology of Alzheimer's disease (AD), but how tau accumulation induces synapse impairment is elusive. By overexpressing human full-length wildtype tau (termed hTau) to mimic tau abnormality as seen in the brain of sporadic AD patients, we found that hTau accumulation activated JAK2 to phosphorylate STAT1 (Signal Transducer and Activator of Transcription 1) at Tyr701 leading to STAT1 dimerization, nuclear translocation and its activation. STAT1 activation suppressed expression of N-methyl-D-aspartate receptors (NMDARs) through direct binding to the specific GAS element of GluN1, GluN2A and GluN2B promoters, while knockdown STAT1 by AAV-Cre in STAT1flox/flox mice or expressing dominant negative Y701F-STAT1 efficiently rescued hTau-induced suppression of NMDARs expression with amelioration of synaptic functions and memory performance. These findings indicate that hTau accumulation impairs synaptic plasticity through JAK2/STAT1-induced suppression of NMDARs expression, revealing a novel mechanism for hTau-associated synapse and memory deficits.

neuroscience↗