IMMUNITY
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2021
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IF 31.745
Run Fang,Qifei Jiang,Yukun Guan,Pengfei Gao,Rui Zhang,Zhen Zhao,Zhengfan Jiang
Summary Activation of the cyclic guanosine monophosphate (GMP)-AMP (cGAMP) sensor STING requires its translocation from the endoplasmic reticulum to the Golgi apparatus and subsequent polymerization. Using a genome-wide CRISPR-Cas9 screen to define factors critical for STING activation in cells, we identified proteins critical for biosynthesis of sulfated glycosaminoglycans (sGAGs) in the Golgi apparatus. Binding of sGAGs promoted STING polymerization through luminal, positively charged, polar residues. These residues are evolutionarily conserved, and selective mutation of specific residues inhibited STING activation. Purified or chemically synthesized sGAGs induced STING polymerization and activation of the kinase TBK1. The chain length and O -linked sulfation of sGAGs directly affected the level of STING polymerization and, therefore, its activation. Reducing the expression of Slc35b2 to inhibit GAG sulfation in mice impaired responses to vaccinia virus infection. Thus, sGAGs in the Golgi apparatus are necessary and sufficient to drive STING polymerization, providing a mechanistic understanding of the requirement for endoplasmic reticulum (ER)-to-Golgi apparatus translocation for STING activation.
研究领域:
免疫学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
CELL
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2025
·
IF 42.5
Ziqiang Zhou,Shicong Zhu,Yaqiang Hong,Guangpu Jin,Rui Ma,Fan Lin,Yiyang Zhang,Hsiang-Ying Lee,Nian Liu
Discrete genomic units can recombine into composite transposons that transcribe and transpose as single units, but their regulation and function are not fully understood. We report that composite transposons harbor bivalent histone marks, with activating and repressive marks in distinct regions. Genome-wide CRISPR-Cas9 screening, using a reporter driven by the hominid-specific composite transposon SVA (SINE [short interspersed nuclear element]-VNTR [variable number of tandem repeats]-Alu) in human cells, identified diverse genes that modify bivalent histone marks to regulate SVA transcription. SVA transcripts are critical for SVA’s cis -regulatory function in selectively contacting and activating long-range gene expression. Remarkably, a subset of bivalent SVAs is activated during erythropoiesis to boost multiple erythroid gene expression, and knocking down these SVAs leads to deficient erythropoiesis. The RNA-dependent cis -regulatory function of SVA activates genes for myelopoiesis and can contribute to aging-associated myeloid-biased hematopoiesis. These results reveal that the cis -regulatory functions of composite transposons are bivalently regulated to control cell fate transitions in development and aging.
研究领域:
分子生物学
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遗传学
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表观遗传学
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发育生物学
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细胞生物学
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血液学
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衰老研究
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产品关联
DOI
PubMed
高影响因子
Cell Metabolism
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2025
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IF 30.9
Tiezhu Shi,Jialiang Shao,Yufeng Ding,Hong Tang,Xiangyin Tan,Sisi Zhou,Shaoqing Yu,Xiang Wang,Guanzhen Yu,Ninghan Feng,Xiongjun Wang
Metabolic adaptations involved in tumor metastasis and immune evasion merit investigation. Here, using in vivo metabolic CRISPR/Cas9 knockout screening, we identified xylulokinase (XYLB) as a tumor suppressor that impairs lung colonialization by producing xylulose 5-phosphate (Xu5P), which promotes CD8 + T cell cytotoxicity. Mechanistically, CD8 + T cells express relatively high levels of solute carrier family 35 member E2 (SLC35E2), a homolog of the plant Xu5P transporter, to facilitate Xu5P uptake and subsequently intensify the pentose phosphate pathway and glycolysis for energy/redox balance. Furthermore, we revealed that Xu5P potentiates CD8 + T cell response by promoting Xu5P-responsive progenitor-like SLC35E2 + CD8 + exhausted T cells via tet methylcytosine dioxygenase 3 (TET3)-mediated DNA demethylation of the Tcf7 promoter. Clinically, elevated XYLB or blood Xu5P correlates with enhanced CD8 + T cell efficacy and reduced metastasis. In murine models, Xu5P supplementation or adopting Xu5P-rich diets synergizes with anti-PD-1 therapy to enhance antitumor immunity. These findings offer insights into the potentiality of dietary interventions for metastatic cancer.
研究领域:
癌症生物学
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免疫学
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代谢工程
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分子生物学
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遗传学
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肿瘤免疫学
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营养科学
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细胞信号传导
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DOI
PubMed
高影响因子
Signal Transduction and Targeted Therapy
·
2025
·Vol. 10
·期 1
·395
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IF 52.7
Liu Yue,Wang Huirui,Zhan Jie,Sun Jiabo,Sun Yan,Fu Xiaojie,Lv Dongxue,Li Xiuyun,Dong Ting,Lou Hongxiang
The widespread clinical application of paclitaxel (PTX) in cancer treatment has been significantly limited by the emergence of drug resistance and the presence of drug-tolerant persister cells. To systematically identify key regulators of this resistance, we conducted a genome-wide CRISPR/Cas9 knockout screen, which revealed that cell division cycle 6 (CDC6) is a critical determinant of cell adhesion-mediated PTX resistance. Furthermore, our results illustrate that CDC6, an essential DNA replication licensing factor, functions through a pathway distinct from previously well-characterized resistance mechanisms. Genetic depletion of CDC6 considerably sensitizes cells, markedly increasing PTX-induced cell death. In addition to its established role in chromosome stability, CDC6 physically interacts with tropomodulin-3 (Tmod3) in the cytoplasmic compartment. This interaction enhances CDC6 protein stability and drives drug resistance phenotypes through the regulation of actin cytoskeleton remodeling and facilitating focal adhesion assembly. In addition, combination treatment with PTX and actin filament inhibitors synergistically enhanced the antitumor efficacy both in vitro and in vivo. Overall, our studies elucidate the mechanisms through which CDC6 functions as a key regulator of PTX resistance and provide a potential therapeutic strategy to increase PTX efficacy through the modulation of the cytoskeletal-adhesion axis.
研究领域:
癌症生物学
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分子肿瘤学
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细胞信号传导
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药物耐药性
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细胞骨架动力学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）