Autophagy
·
2025
·
IF 14.3
Ze Zheng,Cuicui Ji,Hongyu Zhao,Yan G. Zhao
The macroautophagy/autophagy proteins ATG2A and ATG2B transfer lipids for phagophore membrane growth. They also form stable complexes with WDR45 and WDR45B. Our previous study demonstrated that WDR45 and WDR45B mediate autophagosome-lysosome fusion in neural cells. Given the defective autophagosome formation in cells lacking both ATG2s, their role in later autophagy stages is hard to explore. Here, we report that in neuroblastoma-derived Neuro-2a (N2a) cells, knocking down (KD) Atg2a, but not Atg2b, results in significant accumulation of SQSTM1/p62 and MAP1LC3-II/LC3-II, indicating impaired autophagy. Atg2a deficiency does not affect autophagosome formation, but reduces colocalization of autophagosomal LC3 with late endosomal/lysosomal RFP-RAB7, suggesting impaired autophagosome-lysosome fusion. ATG2A interacts with the SNARE proteins STX17, SNAP29, and VAMP8, facilitating their assembly. Overexpression of ATG2A partially rescues the autophagosome-lysosome fusion defects in Wdr45- and Wdr45b-deficient cells. ATG2 and another tether protein, EPG5, function partially redundantly in mediating autophagosome-lysosome fusion. Thus, ATG2A plays a key role in neural autophagy by tethering autophagosomes with lysosomes for fusion.Abbreviations: AAV: adeno-associated virus; ATG2Ar: RNAi-resistant ATG2A; Baf: bafilomycin A1; co-IP: co-immunoprecipitation; CQ: chloroquine; DKD: double knockdown; DKO: double knockout; ER: endoplasmic reticulum; KD: knockdown; KO: knockout; MIL: membrane-impermeable Halo ligand; MPL: membrane-permeable Halo ligand; N2a: Neuro-2a; NC negative control; PG: phagophore; PtdIns3K: phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; TEM: Transmission electron microscopy; TM: transmembrane domain; WT: wild-type.
研究领域:
细胞生物学
·
神经科学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2019
·
IF 4.527
Dan Song,Yu Chen,Binran Wang,Diana Li,Chao Xu,Hong Huang,Saifei Huang,Rong Liu
Bisphenol A (BPA) is an artificial xenoestrogen widely used in consumer products containing polycarbonate plastics and epoxy resins . Exposure to BPA occurs through various channels, including ingestion of contaminated food and water. Autophagy is an important catabolic pathway that plays an important role in liver lipid metabolism . Evidence suggests that BPA exposure causes abnormal lipid droplet accumulation in liver, but the mechanism remains unknown. Here, we investigate the function of BPA in lipid metabolism and autophagy. BPA exposure increases lipid droplet and ROS accumulation which is accompanied by a defect in the fusion of the autophagosome to the lysosome . BPA exposure decreases the translocation of Stx17 to lysosome resulting in the autophagogome-lysosome fusion defect. There is no defect in the formation of the autophagosome indicated by increased LC3-II, p62 level, GFP/mRFP-LC3 ratios and decreased colocalization between LAMP2 with LC3. Mechanistically, BPA exposure reduces autophagy SNARE complex formation. Promoting autophagy by autophagy inducer (Torin2) partially reverses lipid droplet accumulation caused by BPA exposure. In summary, our results demonstrate BPA exposure inhibits autophagy resulting in decreased lipid droplet degradation and increased ROS levels. These results also provide a novel implication between autophagosome-lysosome fusion.
研究领域:
肝病学
·
毒理学
·
细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
MOLECULAR CELL
·
2023
·
IF 16
Xue Huang,Jia Yao,Lu Liu,Jing Chen,Ligang Mei,Jingjing Huangfu,Dong Luo,Xinyi Wang,Changhai Lin,Xiaorong Chen,Yi Yang,Sheng Ouyang,Fujing Wei,Zhuolin Wang,Shaolin Zhang,Tingxiu Xiang,Dante Neculai,Qiming Sun,Eryan Kong,Edward W. Tate,Aimin Yang
p62 is a well-characterized autophagy receptor that recognizes and sequesters specific cargoes into autophagosomes for degradation. p62 promotes the assembly and removal of ubiquitinated proteins by forming p62-liquid droplets. However, it remains unclear how autophagosomes efficiently sequester p62 droplets. Herein, we report that p62 undergoes reversible S -acylation in multiple human-, rat-, and mouse-derived cell lines, catalyzed by zinc-finger Asp-His-His-Cys S -acyltransferase 19 (ZDHHC19) and deacylated by acyl protein thioesterase 1 (APT1). S -acylation of p62 enhances the affinity of p62 for microtubule-associated protein 1 light chain 3 (LC3)-positive membranes and promotes autophagic membrane localization of p62 droplets, thereby leading to the production of small LC3-positive p62 droplets and efficient autophagic degradation of p62-cargo complexes. Specifically, increasing p62 acylation by upregulating ZDHHC19 or by genetic knockout of APT1 accelerates p62 degradation and p62-mediated autophagic clearance of ubiquitinated proteins. Thus, the protein S -acylation-deacylation cycle regulates p62 droplet recruitment to the autophagic membrane and selective autophagic flux, thereby contributing to the control of selective autophagic clearance of ubiquitinated proteins.
研究领域:
细胞生物学
·
分子生物学
·
自噬
✓ 已验证
DOI
PubMed
高影响因子
Frontiers in Immunology
·
2022
·
IF 8.786
Xin Zhao,Wenji Huang,Yanjie Shi,Jiahong Guo,Hehe Xiao,Ning Ji,Jianhua Feng,Huifeng Dang,Jun Zou
PLAAT1 is a member of the PLAAT protein family and plays important roles in tumor suppression, transglutaminase activation and peroxisomal biogenesis. Recently, PLAAT1 has been shown to promote degradation of p53 protein and cellular organelles such as mitochondria, endoplasmic reticulum and lysosome. In this study, we show that PLAAT1 inhibits the production of type I interferon and promotes virus replication in zebrafish. Overexpression of Plaat1 in zebrafish cells suppresses antiviral responses and promotes virus replication. Mechanistically, PLAAT1 interacts with IRF3 and IRF7 to initiate degradation of IRF3 and IRF7, which can be attenuated by 3-methyladenine, an inhibitor of autophagosome. Our study provides novel insights into the functions of PLAAT1 in host immune response to viral infection.
研究领域:
免疫学
·
病毒学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Applied Materials Today
·
2024
·
IF 7.2
Rui Deng,Jibin Wu,Baokang Zhu,Gaoqing Song,Tao Zhou,Musheng Yang,Lingling Pan,Jian Wang,Xuan Zou,Ziquan Lv,Xiaobao Jin,Yinghua Xu,Xuemei Lu,Shuiqing Gui
Hepatocellular carcinoma (HCC) has emerged as one of the most prevalent and highly malignant tumor malignancies worldwide and is characterized by poor prognosis and high mortality. Therefore, effective medications are urgently needed to improve therapeutic effects with HCC. Exosomes are nanoscale vesicles that can transfer cellular information. Owing to their excellent biocompatibility, exosomes are frequently utilized as drug carriers for cancer treatment. Targeted drug delivery systems that modify exosomes to increase targeting have emerged as promising therapeutic platforms in response to the lack of precise targeting by natural exosomes. In this study, HTPP-Exo was successfully constructed by modifying the exosome membrane by connecting sulfhydryl group of HTPP with maleimide in DSPE-PEG2000-Mal, and the antimicrobial peptide M1–8 was included for the first time through co-incubation, thus successfully establishing the HTPP-Exo-M1–8 targeted drug delivery system. The targeting ability of HTPP-Exo-M1–8 was verified by evaluating its in vitro and in vivo targeting of HepG2 cells, and its therapeutic ability was evaluated by its inhibitory effect on HepG2 cells and in situ liver cancer in mice. The results showed that HTPP-Exo-M1–8 targeted drug delivery system could target HepG2 cells in vivo and in vitro , and the survival rate of HepG2 cells was 45 % after HTPP-Exo-M1–8 treatment for 48 h. After in vivo treatment, the volume of HCC in HTPP-Exo-M1–8 group (270.4 mm 3 ) was much smaller than that in control group (969.5 mm 3 ), which achieved the expected purpose of HCC treatment. Further research showed that the targeted drug delivery system HTPP-Exo-M1–8 could be used to treat HCC by inhibiting the lysosome–autophagosome fusion in HepG2 cells. Additionally, there was no obvious toxicity to healthy cells or tissues when HTPP-Exo-M1–8 was used. Overall, the exosome-based targeted drug delivery system HTPP-Exo-M1–8 can treat HCC by targeting and penetrating tumor cells, which provides a new strategy for the treatment of HCC.
研究领域:
肿瘤学
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药学
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生物技术
✓ 已验证
产品关联
DOI
高影响因子
International Journal of Biological Sciences
·
2024
·Vol. 20
·期 8
·2904-2921
·
IF 8.2
Xiong Tianxin,Li Yi,Yang Molin,Huo Bo,Guo Xian,Liu Liyuan,Huang Yanxin,Zhu Xuehai,Hu Qinghua,Wei Xiang,Jiang Ding-Sheng,Yi Xin
Abnormal proliferation of pulmonary artery smooth muscle cells (PASMCs) is one of the critical pathological mechanisms of pulmonary hypertension (PH), and therefore is gradually being adopted as an important direction for the treatment of PH. Metallothioneins (MTs) have been reported to be associated with PH, but the underlying mechanisms are not fully understood. Here, we demonstrated that the expression level of metallothionein 3 (MT3) was significantly increased in pulmonary arterioles from PH patients and chronic hypoxia-induced rat and mouse PH models, as well as in hypoxia-treated human PASMCs. Knockdown of MT3 significantly inhibited the proliferation of human PASMCs by arresting the cell cycle in the G1 phase, while overexpression of MT3 had the opposite effect. Mechanistically, we found that MT3 increased the intracellular zinc (Zn2+) concentration to enhance the transcriptional activity of metal-regulated transcription factor 1 (MTF1), which promoted the expression of autophagy-related gene 5 (ATG5), facilitating autophagosome formation. More importantly, MT3-induced autophagy and proliferation of human PASMCs were largely prevented by knockdown of MTF1 and ATG5. Therefore, in this study, we identified MT3-Zinc-MTF1-ATG5 as a novel pathway that affects PASMC proliferation by regulating autophagosome formation, suggesting that MT3 may be a novel target for the treatment of PH.
研究领域:
心血管疾病
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分子生物学
·
细胞生物学
·
病理生理学
✓ 已验证
DOI
高影响因子
Autophagy
·
2022
·
IF 13.391
Yuhua Zhang,Qiaojun Fang,Hongfeng Wang,Jieyu Qi,Shan Sun,Menghui Liao,Yunhao Wu,Yangnan Hu,Pei Jiang,Cheng Cheng,Xiaoyun Qian,Mingliang Tang,Wei Cao,Shang Xiang,Chen Zhang,Jianming Yang,Xia Gao,Zheng Ying,Renjie Chai
Aminoglycosides exhibit ototoxicity by damaging mitochondria, which in turn generate reactive oxygen species that induce hair cell death and subsequent hearing loss. It is well known that damaged mitochondria are degraded by mitophagy, an important mitochondrial quality control system that maintains mitochondrial homeostasis and ensures cell survival. However, it is unclear whether dysregulation of mitophagy contributes to aminoglycoside-induced hair cell injury. In the current study, we found that PINK1-PRKN-mediated mitophagy was impaired in neomycin-treated hair cells. Our data suggested that mitochondrial recruitment of PRKN and phagophore recognition of damaged mitochondria during mitophagy were blocked following neomycin treatment. In addition, the degradation of damaged mitochondria by lysosomes was significantly decreased as indicated by the mitophagic flux reporter mt-mKeima. Moreover, we demonstrated that neomycin disrupted mitophagy through transcriptional inhibition of Pink1 expression, the key initiator of mitophagy. Moreover, we found that neomycin impaired mitophagy by inducing ATF3 expression. Importantly, treatment with a mitophagy activator could rescue neomycin-treated hair cells by increasing mitophagy, indicating that genetic modulation or drug intervention in mitophagy may have therapeutic potential for aminoglycoside-induced hearing loss.Abbreviations: AAV: adeno-associated virus; ABR: auditory brainstem response; ATF3: activating transcription factor 3; ATOH1/MATH1: atonal bHLH transcription factor 1; BafA1: bafilomycin A1; CCCP: carbonyl cyanide m-chlorophenyl hydrazone; COX4I1/COXIV: cytochrome c oxidase subunit 4I1; CTBP2/RIBEYE: C-terminal binding protein 2; DFP: deferiprone; EGFP: enhanced green fluorescent protein; FOXO3: forkhead box O3; GRIA2/GLUR2: glutamate receptor, ionotropic, AMPA2 (alpha 2); HC: hair cell; HSPD1/HSP60: heat shock protein 1 (chaperonin); IHC: inner hair cell; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MYO7A: myosin VIIA; OPTN: optineurin; OMM: outer mitochondrial membrane; PRKN: parkin RBR E3 ubiquitin protein ligase; PINK1: PTEN induced putative kinase 1; RT-qPCR: real-time quantitative polymerase chain reaction; TOMM20/TOM20: translocase of outer mitochondrial membrane 20; TUNEL: Terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling; USP30: ubiquitin specific peptidase 30; XBP1: X-box binding protein 1.
研究领域:
细胞生物学
·
神经科学
·
耳科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Therapeutics
·
2024
·
IF 3.7
Leping He,Xijun Guo,Wanrong Wang,Weifeng Xu,Xiaoli Feng,Yuanfeng Fu,Yuxi Tian,Zongmao He,Sulan Luo,Jiaolin Bao,Ren-Bo Ding
Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second leading cause of cancer-related death worldwide. More than 30% of CRC patients will experience treatment failure and tumor recurrence after standard-of-care treatment. Therefore, it is important to discover new therapeutic regimens for treating CRC. Repurposing existing clinically used drugs into new anticancer agents represents a feasible way and has become increasingly popular. In this study, the aim is to investigate the anticancer effect of sertraline on CRC and to elucidate its underlying mechanism. The data showed that sertraline exhibited a potent anticancer effect against CRC in vitro and in vivo. Sertraline inhibited Akt- and STAT3-mediated cell proliferation but do not affect several programmed cell deaths in CRC, such as apoptosis, pyroptosis, ferroptosis, and mitophagy. Meanwhile, sertraline induced autophagosome accumulation but blocked autophagic flux in CRC cells. Further investigations reveal that sertraline impeded late autophagic flux at the stage of autolysosomal degradation rather than autophagosome-lysosomal fusion in CRC. Furthermore, it is also demonstrated that sertraline synergistically sensitized chemotherapeutic agents against CRC. Overall, the study reveals the great potential of sertraline as a novel therapeutic candidate for CRC, which is worthy of further development in the future.
研究领域:
肿瘤学
·
药理学
·
分子生物学
·
癌症治疗
✓ 已验证
产品关联
DOI
高影响因子
EUROPEAN POLYMER JOURNAL
·
2022
·
IF 5.546
Zhi Li,Lifen Zhang,Changning Xue,Yuman Zhang,Yao Yu,Xinhong Guo,Zhenzhong Zhang
Hydroxypropyl-β-Cyclodextrin (HP-β-CD) was used to form the HP-β-CD/Oridonin inclusion complex. Then, the novel Multi-loaded nanovesicles systems (NVs) were established to encapsulate both hydrophilic (Trehalose) and hydrophobic drugs (Oridonin inclusion complex) with peptides. NVs had an average size of 224.4 ± 10.84 nm and a zeta potential of 17.83 ± 1.05 mV. Furthermore, these NVs significantly decreased lipid over-accumulation, and reverse the formation of foam cells in RAW264.7 cells. Oridonin and Trehalose in NVs provided significant synergistic effects to inhibit lipid over-accumulation (CI < 1). In addition, NVs could modulate the release of IL-1β, IL-6 and TNF-α, promote the formation of autophagosomes. Taken together, the Multi-loaded NVs may be used as an effective drug delivery system, providing new insights into decrease the formation of foam cells and regulate the inflammation.
研究领域:
药学
·
生物技术
·
细胞生物学
·
药物递送系统
✓ 已验证
产品关联
DOI
高影响因子
Autophagy
·
2022
·
IF 13.391
Haitao Wang,Jianhua Zhang,Haoqiu Liu,Man Wang,Yan Dong,Yijun Zhou,Sek-Man Wong,Kai Xu,Qiufang Xu
Hosts can initiate macroautophagy/autophagy as an antiviral defense response, while viruses have developed multiple ways to evade the host autophagic degradation. However, little is known as to whether viruses can target lipids to subvert autophagic degradation. Here, we show that a low abundant signaling lipid, phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2), is required for rice black-streaked dwarf virus (RBSDV) to evade the autophagic degradation in the insect vector Laodelphax striatellus. RBSDV binds to PtdIns(3,5)P2 and elevates its level through its main capsid protein P10, leading to inhibited autophagy and promoted virus propagation. Furthermore, we show that PtdIns(3,5)P2 inhibits the autophagy pathway by preventing the fusion of autophagosomes and lysosomes through activation of Trpml (transient receptor potential cation channel, mucolipin), an effector of PtdIns(3,5)P2. These findings uncover a strategy whereby a plant virus hijacks PtdIns(3,5)P2 via its viral capsid protein to evade autophagic degradation and promote its survival in insects.
研究领域:
植物病毒学
·
昆虫媒介生物学
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
·
2024
·
IF 12.2
Chanlin Fang,Shanshan Di,Yundong Yu,Peipei Qi,Xinquan Wang,Yuanxiang Jin
The compound 6PPD is widely acknowledged for its antioxidative properties; however, concerns regarding its impact on aquatic organisms have spurred comprehensive investigations. In our study, we advanced our comprehension by revealing that exposure to 6PPD could induce cardiac dysfunction, myocardial injury and DNA damage in adult zebrafish. Furthermore, our exploration unveiled that the exposure of cardiomyocytes to 6PPD resulted in apoptosis and mitochondrial injury, as corroborated by analyses using transmission electron microscopy and flow cytometry. Significantly, our study demonstrated the activation of the autophagy pathway in both the heart of zebrafish and cardiomyocytes, as substantiated by transmission electron microscopy and immunofluorescent techniques. Importantly, the increased the expression of P62 in the heart and cardiomyocytes suggested an inhibition of the autophagic process. The reduction in autophagy flux was also verified through in vivo experiments involving the infection of mCherry-GFP-LC3. We further identified that the fusion of autophagosomes and lysosomes was impaired in the 6PPD treatment group. In summary, our findings indicated that the impaired fusion of autophagosomes and lysosomes hampered the autophagic degradation process, leading to apoptosis and ultimately resulting in cardiac dysfunction and myocardial injury. This study discovered the crucial role of the autophagy pathway in regulating 6PPD-induced cardiotoxicity. Synopsis 6PPD exposure inhibited the autophagic degradation process and induced mitochondrial injury and apoptosis in the heart of adult zebrafish.
研究领域:
毒理学
·
心脏病学
·
细胞生物学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Nature Nanotechnology
·
2025
·
IF 34.9
Huang Wei-Qiang,You Wei,Zhu Ya-Qi,Gao Fan,Wu Zhi-Zhi,Chen Guang,Xiao Jun,Shao Qi,Wang Long-Hai,Nie Xuan,Zhang Ze,Hong Chun-Yan,You Ye-Zi
Autophagosome cancer vaccines can promote cross-presentation of multiple tumour antigens and induce cross-reactive T cell responses. However, so far, there is no effective method for obtaining a highly immunogenic autophagosomal cancer vaccine because autophagosomes, once formed, quickly fuse with lysosomes and cannot easily escape from cells. Here we report a functional Ti 2 NX nanodot that caps the autophagosome membrane lipid phosphatidylinositol-4-phosphate, blocking the fusion of autophagosomes with lysosomes and producing stable nanodot-coated autophagosomes in tumours. The formed nanodot-coated autophagosomes can escape from cancer cells to lymph nodes, where they activate tumour-specific T cells. We show that our approach reduces tumour burden and provide long-term immune surveillance protection for cured mice. This work provides a method for the direct formation of personalized autophagosome-based cancer vaccines in vivo, offering a promising strategy for tumour treatment.
研究领域:
肿瘤学
·
免疫学
·
纳米技术
✓ 已验证
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）