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
Autophagy
·
2016
·
IF 9.108
Na Xie,Kefei Yuan,Li Zhou,Kui Wang,Hai-Ning Chen,Yunlong Lei,Jiang Lan,Qinqin Pu,Wei Gao,Lu Zhang,Guobo Shen,Qifu Li,Hengyi Xiao,Hong Tang,Rong Xiang,Mingliang He,Pinghui Feng,Edouard C. Nice,Yuquan Wei,Haiyuan Zhang,Jiayin Yang,Canhua Huang
Adenosine monophosphate-activated protein kinase (AMPK) is a crucial energy sensor that maintains cellular energy homeostasis. AMPK plays a critical role in macroautophagy/autophagy, and autophagy facilitates hepatitis B virus (HBV) replication. To date, the intrinsic link among AMPK, autophagy and HBV production remains to be elucidated. Here, we demonstrate that PRKAA (a catalytic subunit of AMPK) is activated in response to HBV-induced oxidative stress, which in turn decreases the production of HBV. Mechanistic studies reveal that the autophagy machinery is associated with the inhibitory effect of PRKAA/AMPK on HBV production. Activation of PRKAA/AMPK promotes autolysosome-dependent degradation through stimulation of cellular ATP levels, which then leads to the depletion of autophagic vacuoles. Taken together, our data suggest that the activation of AMPK might be a stress response of host cells to restrict virus production through promotion of autophagic degradation. These findings therefore indicate that AMPK could provide a potential therapeutic target for HBV infection.
研究领域:
病毒学
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2024
·Vol. 25
·期 8
·4493
·
IF 4.9
Jiuge Tang,Dongmei Fang,Jialing Zhong,Min Li
Canonical autophagy is an evolutionarily conserved process that forms double-membrane structures and mediates the degradation of long-lived proteins (LLPs). Noncanonical autophagy (NCA) is an important alternative pathway involving the formation of microtubule-associated protein 1 light chain 3 (LC3)-positive structures that are independent of partial core autophagy proteins. NCA has been defined by the conjugation of ATG8s to single membranes (CASM). During canonical autophagy and NCA/CASM, LC3 undergoes a lipidation modification, and ATG16L1 is a crucial protein in this process. Previous studies have reported that the WDR domain of ATG16L1 is not necessary for canonical autophagy. However, our study found that WDR domain deficiency significantly impaired LLP degradation in basal conditions and slowed down LC3-II accumulation in canonical autophagy. We further demonstrated that the observed effect was due to a reduced interaction between ATG16L1 and FIP200/WIPI2, without affecting lysosome function or fusion. Furthermore, we also found that the WDR domain of ATG16L1 is crucial for chemical-induced NCA/CASM. The results showed that removing the WDR domain or introducing the K490A mutation in ATG16L1 significantly inhibited the NCA/CASM, which interrupted the V-ATPase-ATG16L1 axis. In conclusion, this study highlights the significance of the WDR domain of ATG16L1 for both canonical autophagy and NCA functions, improving our understanding of its role in autophagy.
研究领域:
细胞生物学
·
分子生物学
·
自噬
✓ 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
Autophagy
·
2023
·
IF 13.3
Chaonan Sun,Yuxin Chen,Qianqian Gu,Yuanyuan Fu,Yao Wang,Cui Liu,Huazhong Xie,Yong Liao,Zhihua Zheng,Peiqing Liu,Min Li
ATG4B is a core protein and essential for cleaving precursor MAP1LC3/LC3 or deconjugating lipidated LC3-II to drive the formation of autophagosomes. The protein stability and activity of ATG4B regulated by post-translational modification (ubiquitination) will directly affect macroautophagy/autophagy. However, the mechanism involved in ATG4B ubiquitination is largely unclear. In this study, a new E3 ligase of ATG4B, UBE3C, was identified by mass spectra. UBE3C mainly assembles K33-branched ubiquitin chains on ATG4B at Lys119 without causing ATG4B degradation. In addition, the increased ubiquitination of ATG4B caused by UBE3C overexpression inhibits autophagy flux in both normal and starvation conditions, which might be due to the reduced activity of ATG4B and ATG4B-LC3 interaction. This reduction could be reversed once the lysine 119 of ATG4B was mutated to arginine. More important, under starvation conditions the interaction between ATG4B and UBE3C apparently decreased followed by the removal of the K33-branched ubiquitin chain of ATG4B. Thus, starvation-induced autophagy could be partially suppressed by an increased ubiquitination level of ATG4B. In conclusion, our research reveals a novel modification mode of ATG4B in which UBE3C can fine tune ATG4B activity by specific ubiquitination regulating autophagy without causing ATG4B degradation.
研究领域:
细胞生物学
·
分子生物学
·
生物化学
✓ 已验证
DOI
PubMed
高影响因子
BRITISH JOURNAL OF CANCER
·
2025
·
IF 6.8
Pu Yamin,Xu Fuyan,He Anqi,Li Ru,Wang Xiangxiu,Zhou Liang,Sun Hongbao,Zhang Yiwen,Xia Yong
Background Triple-negative breast cancer (TNBC) presents significant challenges due to its aggressive nature and high propensity for brain metastasis, often exhibiting resistance to standard treatments. In this study, we conducted a preliminary screening of potential therapeutic agents and identified chlorpromazine (CPZ) as a promising candidate for treating TNBC and its brain metastases. Methods The inhibitory activities of CPZ and its combination with several standard treatment drugs were evaluated in preclinical TNBC models. The mechanism of CPZ on TNBC was elucidated using TMT-labeled quantitative proteomics analysis. Results In vivo experiments demonstrated that CPZ robustly suppressed tumor growth and metastasis, particularly in lung and brain models. Importantly, CPZ enhanced the efficacy of standard therapeutic agents such as vinorelbine (NVB) and anti-PD-1 antibody. Mechanistically, CPZ induced G2/M phase arrest and triggered mitochondria-mediated intrinsic apoptosis in TNBC cells. Furthermore, CPZ triggered incomplete autophagy and activated PINK1-Parkin-mediated mitophagy. Inhibiting autophagy/mitophagy augmented CPZ’s anticancer effects, indicating these processes may have cell protective roles. Conclusions Our study highlights the dual function of CPZ in suppressing TNBC growth and metastasis, positioning it as a promising candidate for treating this aggressive cancer. Additionally, targeting autophagy/mitophagy may serve as an effective strategy to enhance anticancer therapies against TNBC.
研究领域:
肿瘤学
·
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Autophagy
·
2024
·
IF 14.6
Xin Chen,Andrey S. Tsvetkov,Han-Ming Shen,Ciro Isidoro,Nicholas T. Ktistakis,Andreas Linkermann,Werner J.H. Koopman,Hans-Uwe Simon,Lorenzo Galluzzi,Shouqing Luo,Daqian Xu,Wei Gu,Olivier Peulen,Qian Cai,David C. Rubinsztein,Jen-Tsan Chi,Donna D. Zhang,Changfeng Li,Shinya Toyokuni,Jinbao Liu,Jong-Lyel Roh,Enyong Dai,Gabor Juhasz,Wei Liu,Jianhua Zhang,Minghua Yang,Jiao Liu,Ling-Qiang Zhu,Weiping Zou,Mauro Piacentini,Wen-Xing Ding,Zhenyu Yue,Yangchun Xie,Morten Petersen,David A. Gewirtz,Michael A. Mandell,Charleen T. Chu,Debasish Sinha,Eftekhar Eftekharpour,Boris Zhivotovsky,Sébastien Besteiro,Dmitry I. Gabrilovich,Do-Hyung Kim,Valerian E. Kagan,Hülya Bayir,Guang-Chao Chen,Scott Ayton,Jan D. Lünemann,Masaaki Komatsu,Stefan Krautwald,Ben Loos,Eric H. Baehrecke,Jiayi Wang,Jon D. Lane,Junichi Sadoshima,Wan Seok Yang,Minghui Gao,Christian Münz,Michael Thumm,Martin Kampmann,Di Yu,Marta M. Lipinski,Jace W. Jones,Xuejun Jiang,Herbert J. Zeh,Rui Kang,Daniel J. Klionsky,Guido Kroemer,Daolin Tang
Macroautophagy/autophagy is a complex degradation process with a dual role in cell death that is influenced by the cell types that are involved and the stressors they are exposed to. Ferroptosis is an iron-dependent oxidative form of cell death characterized by unrestricted lipid peroxidation in the context of heterogeneous and plastic mechanisms. Recent studies have shed light on the involvement of specific types of autophagy (e.g. ferritinophagy, lipophagy, and clockophagy) in initiating or executing ferroptotic cell death through the selective degradation of anti-injury proteins or organelles. Conversely, other forms of selective autophagy (e.g. reticulophagy and lysophagy) enhance the cellular defense against ferroptotic damage. Dysregulated autophagy-dependent ferroptosis has implications for a diverse range of pathological conditions. This review aims to present an updated definition of autophagy-dependent ferroptosis, discuss influential substrates and receptors, outline experimental methods, and propose guidelines for interpreting the results.Abbreviation: 3-MA:3-methyladenine; 4HNE: 4-hydroxynonenal; ACD: accidentalcell death; ADF: autophagy-dependentferroptosis; ARE: antioxidant response element; BH2:dihydrobiopterin; BH4: tetrahydrobiopterin; BMDMs: bonemarrow-derived macrophages; CMA: chaperone-mediated autophagy; CQ:chloroquine; DAMPs: danger/damage-associated molecular patterns; EMT,epithelial-mesenchymal transition; EPR: electronparamagnetic resonance; ER, endoplasmic reticulum; FRET: Försterresonance energy transfer; GFP: green fluorescent protein;GSH: glutathione;IF: immunofluorescence; IHC: immunohistochemistry; IOP, intraocularpressure; IRI: ischemia-reperfusion injury; LAA: linoleamide alkyne;MDA: malondialdehyde; PGSK: Phen Green™ SK;RCD: regulatedcell death; PUFAs: polyunsaturated fatty acids; RFP: red fluorescentprotein;ROS: reactive oxygen species; TBA: thiobarbituricacid; TBARS: thiobarbituric acid reactive substances; TEM:transmission electron microscopy.
研究领域:
细胞生物学
·
病理学
✓ 已验证
DOI
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
JOURNAL OF CELL BIOLOGY
·
2023
·Vol. 222
·期 5
·e202201068
·
IF 7.8
Wang Xinyi,Jiang Xiao,Li Boran,Zheng Jiahua,Guo Jiansheng,Gao Lei,Du Mengjie,Weng Xialian,Li Lin,Chen She,Zhang Jingzi,Fang Lei,Liu Ting,Wang Liang,Liu Wei,Neculai Dante,Sun Qiming
Macroautophagy (autophagy) utilizes a serial of receptors to specifically recognize and degrade autophagy cargoes, including damaged organelles, to maintain cellular homeostasis. Upstream signals spatiotemporally regulate the biological functions of selective autophagy receptors through protein post-translational modifications (PTM) such as phosphorylation. However, it is unclear how acetylation directly controls autophagy receptors in selective autophagy. Here, we report that an ER-phagy receptor FAM134B is acetylated by CBP acetyltransferase, eliciting intense ER-phagy. Furthermore, FAM134B acetylation promoted CAMKII-mediated phosphorylation to sustain a mode of milder ER-phagy. Conversely, SIRT7 deacetylated FAM134B to temper its activities in ER-phagy to avoid excessive ER degradation. Together, this work provides further mechanistic insights into how ER-phagy receptor perceives environmental signals for fine-tuning of ER homeostasis and demonstrates how nucleus-derived factors are programmed to control ER stress by modulating ER-phagy.
研究领域:
细胞生物学
·
分子生物学
·
生物化学
✓ 已验证
DOI
PubMed
高影响因子
Frontiers in Aging Neuroscience
·
2020
·
IF 4.364
Zhao Yueyang,Long Zhimin,Ding Ya,Jiang Tingting,Liu Jiajun,Li Yimin,Liu Yuanjie,Peng Xuehua,Wang Kejian,Feng Min,He Guiqiong
Dihydroartemisinin (DHA) is an active metabolite of sesquiterpene trioxane lactone extracted from Artemisia annua, which is used to treat malaria worldwide. DHA can activate autophagy, which is the main mechanism to remove the damaged cell components and recover the harmful or useless substances from eukaryotic cells and maintain cell viability through the autophagy lysosomal degradation system. Autophagy activation and autophagy flux correction are playing an important neuroprotective role in the central nervous system, as they accelerate the removal of toxic protein aggregates intracellularly and extracellularly to prevent neurodegenerative processes, such as Alzheimer’s disease (AD). In this study, we explored whether this mechanism can mediate the neuroprotective effect of DHA on the AD model in vitro and in vivo. Three months of DHA treatment improved the memory and cognitive impairment, reduced the deposition of amyloid β plaque, reduced the levels of Aβ40 and Aβ42, and ameliorated excessive neuron apoptosis in APP/PS1 mice brain. In addition, DHA treatment increased the level of LC3 II/I and decreased the expression of p62. After Bafilomycin A1 and Chloroquine (CQ) blocked the fusion of autophagy and lysosome, as well as the degradation of autolysosomes (ALs), DHA treatment increased the level of LC3 II/I and decreased the expression of p62. These results suggest that DHA treatment can correct autophagic flux, improve autophagy dysfunction, inhibit abnormal death of neurons, promote the clearance of amyloid-β peptide (Aβ) fibrils, and have a multi-target effect on the neuropathological process, memory and cognitive deficits of AD.
研究领域:
神经科学
·
药理学
·
分子生物学
·
神经退行性疾病
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Autophagy
·
2024
·
IF 14.6
Tian Zhang,Ke-Gang Linghu,Jia Tan,Mingming Wang,Diao Chen,Yan Shen,Junchao Wu,Mingjun Shi,Yuxia Zhou,Lei Tang,Lirong Liu,Zheng-Hong Qin,Bing Guo
Obesity is one of the most common metabolic diseases around the world, which is distinguished by the abnormal buildup of triglycerides within adipose cells. Recent research has revealed that autophagy regulates lipid mobilization to maintain energy balance. TIGAR (Trp53 induced glycolysis regulatory phosphatase) has been identified as a glycolysis inhibitor, whether it plays a role in the metabolism of lipids is unknown. Here, we found that TIGAR transgenic (TIGAR+/+) mice exhibited increased fat mass and trended to obesity phenotype. Non-target metabolomics showed that TIGAR caused the dysregulation of the metabolism profile. The quantitative transcriptome sequencing identified an increased levels of LRRK2 and RAB7B in the adipose tissue of TIGAR+/+ mice. It was confirmed in vitro that TIGAR overexpression increased the levels of LRRK2 by inhibiting polyubiquitination degradation, thereby suppressing macroautophagy and chaperone-mediated autophagy (CMA) while increasing lipid accumulation which were reversed by the LRRK2 inhibitor DNL201. Furthermore, TIGAR drove LRRK2 to interact with RAB7B for suppressing lysosomal degradation of lipid droplets, while the increased lipid droplets in adipocytes were blocked by the RAB7B inhibitor ML282. Additionally, fat-specific TIGAR knockdown of TIGAR+/+ mice alleviated the symptoms of obesity, and adipose tissues-targeting superiority DNL201 nano-emulsion counteracted the obesity phenotype in TIGAR+/+ mice. In summary, the current results indicated that TIGAR performed a vital function in the lipid metabolism through LRRK2-mediated negative regulation of macroautophagy and CMA in adipocyte. The findings suggest that TIGAR has the potential to serve as a viable therapeutic target for treating obesity and its associated metabolic dysfunction.
研究领域:
代谢
·
分子生物学
·
细胞生物学
·
药理学
✓ 已验证
DOI
PubMed
高影响因子
RESEARCH IN MICROBIOLOGY
·
2022
·
IF 3.946
Jiawen Du,He Zhao,Mengsen Zhu,Yixuan Dong,Liping Peng,Jianrong Li,Qiang Zhao,Qilin Yu,Mingchun Li
The unfolded protein response (UPR) is an important pathway to prevent endoplasmic reticulum (ER) stress in eukaryotic cells. In Saccharomyces cerevisiae , Ire1 is a key regulatory factor required for HAC1 gene splicing for further production of functional Hac1 and activation of UPR gene expression. Autophagy is another mechanism involved in the attenuation of ER stress by ER-phagy, and Atg8 is a core protein in autophagy. Both autophagy and UPR are critical for ER stress response, but whether they act individually or in combination in Candida albicans is unknown. In this study, we explored the interaction between Ire1 and the autophagy protein Atg8 for the ER stress response by constructing the atg8 Δ/Δ ire1 Δ/Δ double mutant in the pathogenic fungus C. albicans . Compared to the single mutants atg8 Δ/Δ or ire1 Δ/Δ, atg8 Δ/Δ ire1 Δ/Δ exhibited much higher sensitivity to various ER stress-inducing agents and more severe attenuation of UPR gene expression under ER stress. Further investigations showed that the double mutant had a defect in ER-phagy, which was associated with attenuated vacuolar fusion under ER stress. This study revealed that Ire1 and Atg8 in combination function in the activation of the UPR and ER-phagy to maintain ER homeostasis under ER stress in C. albicans .
研究领域:
分子生物学
·
微生物学
·
细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）