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細(xì)胞研究

CELL RESEARCH

ISSN：1001-0602
發(fā)文量： 61
影響因子：20.507
JCR分區(qū)：Q1
ISSN：1001-0602
Number of publications: 61
Impact factor： 20.507
JCR partition：Q1

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AMPK targets PDZD8 to trigger carbon source shift from glucose to glutamine

The shift of carbon utilization from primarily glucose to other nutrients is a fundamental metabolic adaptation to cope with decreased blood glucose levels and the consequent decline in glucose oxidation. AMP-activated protein kinase (AMPK) plays crucial roles in this metabolic adaptation. However, the underlying mechanism is not fully understood. Here, we show that PDZ domain containing 8 (PDZD8), which we identify as a new substrate of AMPK activated in low glucose, is required for the low glucose-promoted glutaminolysis. AMPK phosphorylates PDZD8 at threonine 527 (T527) and promotes the interaction of PDZD8 with and activation of glutaminase 1 (GLS1), a rate-limiting enzyme of glutaminolysis. In vivo, the AMPK-PDZD8-GLS1 axis is required for the enhancement of glutaminolysis as tested in the skeletal muscle tissues, which occurs earlier than the increase in fatty acid utilization during fasting. The enhanced glutaminolysis is also observed in macrophages in low glucose or under acute lipopolysaccharide (LPS) treatment. Consistent with a requirement of heightened glutaminolysis, the PDZD8-T527A mutation dampens the secretion of pro-inflammatory cytokines in macrophages in mice treated with LPS. Together, we have revealed an AMPK-PDZD8-GLS1 axis that promotes glutaminolysis ahead of increased fatty acid utilization under glucose shortage.

引用量：149發(fā)表時(shí)間：2024年
Structural basis for linker histone H5–nucleosome binding and chromatin fiber compaction

The hierarchical packaging of chromatin fibers plays a critical role in gene regulation. The 30-nm chromatin fibers, a central-level structure bridging nucleosomal arrays to higher-order organizations, function as the first level of transcriptional dormant chromatin. The dynamics of 30-nm chromatin fiber play a crucial role in biological processes related to DNA. Here, we report a 3.6-angstrom resolution cryogenic electron microscopy structure of H5-bound dodecanucleosome, i.e., the chromatin fiber reconstituted in the presence of linker histone H5, which shows a two-start left-handed double helical structure twisted by tetranucleosomal units. An atomic structural model of the H5-bound chromatin fiber, including an intact chromatosome, is built, which provides structural details of the full-length linker histone H5, including its N-terminal domain and an HMG-motif-like C-terminal domain. The chromatosome structure shows that H5 binds the nucleosome off-dyad through a three-contact mode in the chromatin fiber. More importantly, the H5-chromatin structure provides a fine molecular basis for the intra-tetranucleosomal and inter-tetranucleosomal interactions. In addition, we systematically validated the physiological functions and structural characteristics of the tetranucleosomal unit through a series of genetic and genomic studies in Saccharomyces cerevisiae and in vitro biophysical experiments. Furthermore, our structure reveals that multiple structural asymmetries of histone tails confer a polarity to the chromatin fiber. These findings provide structural and mechanistic insights into how a nucleosomal array folds into a higher-order chromatin fiber with a polarity in vitro and in vivo.

引用量：114發(fā)表時(shí)間：2024年
Structural basis of tethered agonism and G protein coupling of protease-activated receptors

Protease-activated receptors (PARs) are a unique group within the G protein-coupled receptor superfamily, orchestrating cellular responses to extracellular proteases via enzymatic cleavage, which triggers intracellular signaling pathways. Protease-activated receptor 1 (PAR1) is a key member of this family and is recognized as a critical pharmacological target for managing thrombotic disorders. In this study, we present cryo-electron microscopy structures of PAR1 in its activated state, induced by its natural tethered agonist (TA), in complex with two distinct downstream proteins, the Gq and Gi heterotrimers, respectively. The TA peptide is positioned within a surface pocket, prompting PAR1 activation through notable conformational shifts. Contrary to the typical receptor activation that involves the outward movement of transmembrane helix 6 (TM6), PAR1 activation is characterized by the simultaneous downward shift of TM6 and TM7, coupled with the rotation of a group of aromatic residues. This results in the displacement of an intracellular anion, creating space for downstream G protein binding. Our findings delineate the TA recognition pattern and highlight a distinct role of the second extracellular loop in forming β-sheets with TA within the PAR family, a feature not observed in other TA-activated receptors. Moreover, the nuanced differences in the interactions between intracellular loops 2/3 and the Gα subunit of different G proteins are crucial for determining the specificity of G protein coupling. These insights contribute to our understanding of the ligand binding and activation mechanisms of PARs, illuminating the basis for PAR1’s versatility in G protein coupling.

引用量：78發(fā)表時(shí)間：2024年
Bitter taste receptor TAS2R14 activation and G protein assembly by an intracellular agonist

The density maps and structure coordinates have been deposited to the Electron Microscopy Database (EMDB) and the Protein Data Bank (PDB) with accession numbers: EMD-60608 and 9IIX for the overall structure of Ggust-coupled TAS2R14 complex; EMD-60607 and 9IIW for the refined structure of TAS2R14 from the Ggust-coupled complex; EMD-60626 and 9IJ9 for the overall structure of Gi-coupled TAS2R14 complex; EMD-60627 and 9IJA for the refined structure of TAS2R14 from the Gi-coupled complex.

引用量：15發(fā)表時(shí)間：2024年
Molecular insights into the inhibition of proton-activated chloride channel by transfer RNA

Structure and map were deposited to the Protein Data Bank (8H8D, 8H8E, 8H8F) and Electron Microscopy Data Bank (EMD-34543, EMD-34544, EMD-34545). RNA-seq data were deposited to the GEO (NCBI) database (GSE216637).

引用量：14發(fā)表時(shí)間：2024年
No pain, no gain — how nociceptors orchestrate tissue repair

Pain-sensing peripheral neurons, nociceptors, exert control over many aspects of the immune response through various means, including the secretion of immunomodulatory molecules. Adding to the growing list of such interactions, a recent article by Lu et al. reported that a nociceptive neuropeptide, calcitonin gene-related peptide, induces thrombospondin-1 expression in macrophages and neutrophils, limiting their pro-inflammatory functions and promoting tissue repair after injury.

引用量：12發(fā)表時(shí)間：2024年
All-in-one Hangzhou Protocol: killing four birds with one stone

In a recent study published in The New England Journal of Medicine, researchers developed an innovative “all-in-one” treatment protocol that combines CD7 chimeric antigen receptor T-cell therapy with subsequent haploidentical hematopoietic stem cell transplantation. This approach significantly advances the treatment of CD7+ hematological malignancies by eliminating the need for myeloablative chemotherapy and immunosuppressants for graft-versus-host disease prophylaxis.

引用量：11發(fā)表時(shí)間：2024年
Deletion of V483 in the spike confers evolutionary advantage on SARS-CoV-2 for human adaptation and host-range expansion after a prolonged pandemic

Dear Editor,

引用量：10發(fā)表時(shí)間：2024年
Illuminating the path to pancreatic cancer

Braxton and colleagues used 3D histological reconstruction and multi-region genomic analysis to understand the microanatomy and model the progression of pancreatic intraepithelial neoplasias (PanINs), precursors of pancreatic ductal adenocarcinoma (PDAC). Their study revealed the unexpected prevalence, spatial distribution, and genetic heterogeneity of PanINs, illuminating their developmental trajectories toward PDAC.

引用量：10發(fā)表時(shí)間：2024年
Tumor microenvironment squeezes out the juice from T cells

Escaping the immune response is a major prerequisite for tumor to emerge and progress, and many different mechanisms are in place within the tumor microenvironment (TME) to reach this aim, including the induction of CD8+ T cell exhaustion. In a recent publication in Cell, Zhang and colleagues showed that biomechanical stress occurring in the TME enforces CD8+T cell exhaustion through the expression of the transcription factor Osr2 that acts as an epigenetic regulator.

引用量：10發(fā)表時(shí)間：2024年

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