Biology subjects

Che, L.

Publications and source records attributed to Che, L..

7 recordsLinked to original sources

bioRxiv2025

Virus-host interactome reveals host cellular pathways perturbed by tick-borne encephalitis virus infection

Tick-borne encephalitis virus (TBEV) poses an increasingly significant threat to public health. Here, we delved into the virus-host interactome and discovered that TBEV has a profound impact on multiple host cellular pathways. Viral pre-membrane protein (prM), non-structural proteins NS1, NS2B3, NS4A, and NS5 remodel the hosts innate immune responses. PrM and NS2B3 are involved in autophagy, NS4A is associated with neurodegenerative diseases, and NS5 participates in spliceosome dynamics, ribosomal biogenesis, cell cycle regulation, and DNA damage response. Notably, TBEV infection causes G0/G1 cell cycle arrest in host cells. NS5 interacts with histone acetyltransferase P300 to upregulate P16 expression, suppressing CDK4 and resulting in cell cycle arrest. Elevated P16 and reduced CDK4 levels were observed in TBEV-infected brain organoids. The P300 inhibitors and CDK4 agonist can reverse virus-induced cell cycle arrest and inhibit viral replication. Further analysis uncovered potential antiviral targets like KAT6A, XIAP, and RIOK1/BRD9. These findings provide valuable insights into TBEV pathogenicity and hold promise for antiviral drug development.

microbiology↗

bioRxiv2024

BRUCE liver-deficiency potentiates MASLD/MASH in PTEN liver-deficient background by impairment of mitochondrial metabolism in hepatocytes and activation of STAT3 signaling in hepatic stellate cells

Metabolic dysfunction-associated steatotic liver disease (MASLD) is currently the most common liver disease, affecting up to 25% of people worldwide, featuring excessive fat accumulation in hepatocytes. Its advanced form, metabolic dysfunction-associated steatohepatitis (MASH), is a serious disease with hepatic inflammation and fibrosis, increasing the need for liver transplants. However, the pathogenic mechanism of MASLD and MASH is not fully understood. We reported that BRUCE (BIRC6) is a liver cancer suppressor and is downregulated in MASLD/MASH patient liver specimens, though the functional role of BRUCE in MASLD/MASH remains to be elucidated. To this end, we generated liver-specific double KO (DKO) mice of BRUCE and PTEN, a major tumor suppressor and MASLD/MASH suppressor. By comparing liver histopathology among 2-3-month-old mice, there were no signs of MASLD or MASH in BRUCE liver-KO mice and only onset of steatosis in PTEN liver-KO mice. Interestingly, DKO mice had developed robust hepatic steatosis with inflammation and fibrosis. Further analysis of mitochondrial function with primary hepatocytes found moderate reduction of mitochondrial respiration, ATP production and fatty acid oxidation in BRUCE KO and the greatest reduction in DKO hepatocytes. Moreover, aberrant activation of pro-fibrotic STAT3 signaling was found in hepatic stellate cells (HSCs) in DKO mice which was prevented by administered STAT3-specific inhibitor (TTI-101). Collectively, the data demonstrates by maintaining mitochondrial metabolism BRUCE works in concert with PTEN to suppress the pro-fibrogenic STAT3 activation in HSCs and consequentially prevent MASLD/MASH. The findings highlight BRUCE being a new co-suppressor of MASLD/MASH.

molecular biology↗

bioRxiv2024

The segmented flavivirus Alongshan virus reduces mitochondrial mass via degrading STAT2 to suppress innate immune response

Alongshan virus (ALSV) is a newly discovered pathogen of the Flaviviridae family, characterized by a multi-segmented genome distantly related to the canonical flaviviruses. Understanding the pathogenic mechanism of the emerging segmented flavivirus is crucial for the development of intervention strategies. Here we show that ALSV can infect multiple mammalian cells and induces the expression of antiviral genes. Moreover, ALSV is sensitive to IFN-{beta} and possesses the ability to counteract type I IFN response. Mechanistically, ALSVs nonstructural protein NSP1 binds to and degrades human STAT2 through an autophagy pathway in a species-dependent manner, resulting in direct inhibition of the expression of interferon-stimulated genes (ISGs). Specifically, NSP1 methyltransferase domain binds to the key sites of F175/R176 located in coiled-coil domain of STAT2. Moreover, NSP1-mediated degradation of STAT2 results in a reduction in mitochondrial mass by disrupting mitochondrial dynamics to induce mitophagy and inhibiting mitochondrial biogenesis, thereby suppressing the innate immune response. Interestingly, inhibiting mitophagy using 3-Methyladenine and enhancing mitochondrial biogenesis using the PPAR{gamma} agonist pioglitazone can reverse NSP1-mediated inhibition of ISGs, suggesting that promoting mitochondrial mass presents an effective antiviral strategy. Our findings elucidate the intricate regulatory crosstalk between ALSV and the hosts innate immune response, providing valuable insights into the pathogenesis and intervention strategy of emerging segmented flavivirus.

microbiology↗

bioRxiv2023

Tumors cells with mismatch repair deficiency induce hyperactivation of Pyroptosis resistant to cell membrane damage but are more sensitive to Co-treatment of IFN-γ and TNF-α to PANoptosis

Hypermutated neoantigens in cancers with DNA mismatch repair deficiency (dMMR) are prerequisite for favorable clinical responses to immune-checkpoint blockade (ICB) therapy. However, TMB is not significantly associated with favorable prognosis from Preclinical and clinical studies. It implys that except for TMB, other mechanisms should be needed to contribute to successful cancer immunotherapy. We found that the hyperactivation of PANoptotic effective molecules in dMMR tumor cells caused cell membrane damage, and induced ESCRT mediated membrane repair, and protectd tumor cells from the damage caused by Triton X100, while DNA mismatch repair proficient (pMMR) tumor cells were sensitive to Triton X100 mediating cell membrane damage due to the lack of ESCRT mediated membrane repair. There were hyperactivation of GSDMD, GSDME and p-MLKL in dMMR tumor cells. Co-treatment of IFN-{gamma} and TNF- induced rapid death of dMMR tumor cells by inducing PANoptosis including pyroptosis, apoptosis not necrosis. pMMR tumor cells had defects in PANoptosis pathway and were resistant to co-treatment of IFN-{gamma} and TNF-. In conclusion, we can activate immune cells to release IFN-{gamma} and TNF- to overcome resistance to ICB treatment.

cancer biology↗

bioRxiv2023

HBV rewires liver cancer signaling by altering PP2A complexes

Infection by hepatitis B virus (HBV) increases risk for liver cancer by inducing inflammation, cellular stress and cell death. To elucidate the molecular pathways by which HBV promotes cancer development and progression, we used affinity purification mass spectrometry to comprehensively map a network of 145 physical interactions between HBV and human host proteins in hepatocellular carcinoma (HCC). We find that viral proteins target host factors that are preferentially mutated in non-HBV-associated HCC, implicating cancer pathways whose interaction with HBV plays a role in HCC. Focusing on proteins that directly interact with the HBV oncoprotein X (HBx), we show that HBx remodels the PP2A phosphatase complex, altering its effect on tumor signaling. HBx excludes striatin-family regulatory subunits from PP2A, causing Hippo kinase activation and unmasking a requirement for mTOR complex 2 to maintain expression of the YAP oncoprotein in HCC. Thus, HBV rewires HCC to expose potentially targetable signaling dependencies. SignificancePrecision medicine has revolutionized cancer treatment but remains elusive for HCC. We used proteomics to define HBV/host interactions and integrated them with HCC mutations. The results implicate modifiers of HCC behavior via remodeling of host complexes and illuminate new biological mechanisms in advanced disease for therapeutic investigation.

cancer biology↗

bioRxiv2022

GutMeta: online microbiome analysis and interactive visualization with build-in curated human gut microbiome database

BackgroundThe human gut microbiome is associated with numerous human diseases. The whole-genome shotgun metagenomics sequencing helps accumulate a massive amount of gut microbiome data. However, few curated integrated platforms are available to explore the vast dataset. Advances in data generation pose new challenges to researchers attempting to analyze, visualize, and reuse published data. ResultGutMeta (human GUT whole-genome shotgun METAgenomics data analysis platform) is a one-stop online human gut metagenomic research platform that integrates a curated database, analyses, and visualizations. First, we built the Human Gut Metagenomics Database (HGMD), which contained taxonomy profiling and metadata of the metagenomics. HGMD collected the published human gut microbiome samples with whole metagenome shotgun (WMGS) sequencing data and consistently performed taxonomy classification using MetaPhlan3 for each sample. The various related metadata information was curated, and phenotypes were according to the MeSH ID. At this moment, HGMD contains 20,898 samples from 91 projects related to 65 diseases. Embedded tools could help users to explore the samples by keywords. Second, GutMeta provides researchers with user-friendly metagenomics analysis modules, including community diversity calculation, differential testing, dimension reduction, disease classifier construction, etc. Then, GutMeta provides corresponding interactive visualizations which can download as Scalable Vector Graphics (SVG), providing high-quality images. Further, GutMeta supplies two additional visualizations for the multi-level taxonomy overview for advanced investigations. GutMeta also supports online editing, including attribute adjustment, recoloring, reordering, and drag-and-drop. Third, GutMeta supports users in building their metagenomics analysis workspaces, including standard profiles uploading and built-in HGMD data import for online customized analyses and visualization. ConclusionGutMeta offers a solution to improve reproducibility in metagenomic research, with the standardized procedure from input data to downstream analysis and visualization. GutMeta is a free access analysis platform that integrates human gut WMGS sequencing data, nine online bioinformatics analysis and data visualization modules/pipelines, and a customized workspace. GutMeta is avaiable at https://GutMeta.deepomics.org.

bioinformatics↗

bioRxiv2019

Millet-based supplement restored microbiota diversity of acute undernourished pigs

The strong connection between undernutrition and gut microbiota (GM) has enabled microbiota-targeting to become an evolving strategy, which witnessed urgent need for fortified formula of supplementary food in undernutrition therapy. Using undernourished pigs as models, we investigated how corn- and millet-based nutritional supplement acted differently in modulating microbiota. Undernourished pigs at age of 9 weeks were fed with pure maize diet (Maize), corn-based (CSB+) and millet-based (MSB+) supplementary food for 3 weeks. Compared with Maize group, both CSB+ and MSB+ improved serum total protein and globulin level, but no physiological improvement was observed by short-term food intervention. MSB+ shown superior influence on GM immaturity which were more normally-grown like at both structural and functional level. Higher level of Bacteriodetes, Firmicutes and lower level of Preteobacteria were detected in MSB+ fed piglets in contrast with CSB+. Lachnospira.spp was significantly raised after nutritional intervention, indicating high correlation with the undernutrition-associated phenotype. Thus, especially from the GM aspect, millet could be one promising source to help undernourished children reconstruct balanced microbiota in short therapeutic term.

microbiology↗