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Abstract: Almost all the reported cryo-EM structures of eukaryotic voltage-gated sodium (Na v ) channels, including those of human Na v 1.1-Na v 1.8, represent various inactivated states that are characteristic of non-conductive pore domain (PD) and voltage-sensing domains (VSDs) activated to varying degrees. To capture an open-state Na v structure, we treated purified human Na v 1.7 with veratridine...
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Abstract: Single-particle cryo-electron microscopy (cryo-EM) typically requires the acquisition and analysis of a large number of micrographs to achieve high-resolution three-dimensional (3D) reconstructions of biological macromolecules. In this study, we demonstrate that when sample quality is sufficiently high, near-atomic resolution 3D density maps can be obtained using particle images from a single...
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Abstract: Itaconate accumulates and manifests antibacterial activity in macrophages upon bacterial infection. Convincing evidence substantiates that itaconate transports across the plasma membrane and vacuolar membrane. But the molecular bases underlying the bidirectional transport of itaconate across membranes and how it affects intracellular bacterial replication remain elusive. Here, we identify...
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Abstract: The functional diversification of biosynthetic enzymes underlies the chemical richness of natural products, yet how primary metabolic enzymes evolve to acquire specialized functions in secondary metabolism remains elusive. Here, we report a tripartite enzyme complex from oral Streptococcus species—comprising 3-hydroxy-3-methylglutaryl (HMG)-CoA synthase (HMGS), acetyl-CoA acetyltransferase...
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Abstract: The tumor glycocalyx forms a protective shield that masks checkpoint proteins and compromises the efficacy of immunotherapies. While the bacterial protease StcE can degrade this barrier by cleaving O-glycosylated mucin domains, its therapeutic potential is hindered by off-target toxicity and high immunogenicity. To overcome these limitations, we developed a biomimetic platform of cell membrane...
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Abstract: Clear cell renal cell carcinoma (ccRCC) is an aggressive malignancy with a complex and immunosuppressive tumor microenvironment (TME). While aggrephagy, a selective autophagy process, has been linked to cancer, its role in ccRCC remains unclear. Through integrated multi-omics analysis of single-cell and bulk sequencing data, we constructed the first aggrephagy activity atlas in ccRCC TME,...
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Matrix Stiffness Induces Midnolin-dependent Lamin B1 Degradation to Control Myoblast Differentiation
Abstract: Cells decode mechanical cues to direct fate decisions through nuclear remodeling, yet nuclear adaptors to mechanical signals remain elusive. Here, we show that soft matrix suppresses myoblast differentiation and induces nuclear abnormality within 30 minutes, accompanied by a >60% reduction in lamin B1 proteins levels. Mechanistically, midnolin interacts with lamin B1 and mediates... -
Abstract: SUN1/2, core components of the linker of nucleoskeleton and cytoskeleton (LINC) complex, transmit extracellular mechanical forces to nuclear lamina and chromatin. However, their role in regulating peripheral chromatin in mechanosensing and mechanoadaptation remains unclear. Using CRISPR/Cas9-mediated knockout of Sun1 or Sun2 in myoblasts, we identified a SUN1/2-dependent mechano-feedback...
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Abstract: Alternative tandem transcription initiation (ATI) is a pervasive mechanism of gene regulation, yet its genetic impact on human disease remains largely unknown. Here, we systematically quantified genetic regulation of ATI across 25,859 samples from 49 human normal tissues and 33 tumor tissues. We identified ~0.4 million 5′ UTR ATI quantitative trait loci (5′aQTLs) in 5,295 genes, with 32%...