EMBO REPORTS
·
2025
·
IF 6.2
LiYuanyuan,ChengShuyang,JinXu,WuRuoxuan,GuoYiyi,WuDezhi,DongJie
Plants have evolved intricate strategies to cope with various abiotic stresses. Ubiquitin-mediated protein degradation plays a key role in plant development as well as abiotic stress tolerance. In this study, we identify LAO1, an F-box protein with unknown function, as a negative regulator of plant fitness during nitrogen starvation. DOMINANT SUPPRESSOR OF KAR 2 (DSK2) interacts with and mediates the autophagic degradation of LAO1 protein during nitrogen starvation. The loss of LAO1 improves the fitness of an autophagy-deficient mutant, atg5-1, under nitrogen starvation. Intriguingly, mutations in DSK2 facilitate rather than reduce plant growth after nitrogen starvation. This unexpected effect of DSK2 knockout led us to discover that DSK2 also interacts with and degrades a group of class I TCP transcription factors. Phenotypic observations demonstrate that class I TCPs are crucial for plant adaptation to nitrogen starvation. Moreover, genetic analyses indicate that class I TCPs function downstream of LAO1 and counteract its negative effects. Collectively, our findings unveil a previously undescribed regulatory network governing plant fitness during nitrogen starvation.
研究领域:
植物学
·
分子生物学
✓ 已验证
产品关联
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
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分子生物学
·
自噬
✓ 已验证
DOI
PubMed
高影响因子
LIFE SCIENCES
·
2025
·
IF 5.1
Zexuan Li,Xinyue Deng,Yanna Cao,Hongbo Xu,Jiangang Wang,Lamei Yuan,Hao Deng
Aim Congenital cataract, a lenticular opacity diagnosed at birth or early in the postnatal period, often causes visual impairment. The pathogenic mechanisms of various cataract-associated variants are complex and diverse, and current knowledge is insufficient. This study aimed to determine the molecular etiology of congenital nuclear cataract in a Han-Chinese family and to reveal the pathogenic mechanisms of common cataract-associated variants with unclear mechanisms. Methods Genetic analysis including whole exome sequencing and bioinformatics was conducted in the family. Functional analysis was performed to elucidate the changes in protein cellular distribution, degradation, and function induced by the variants. Results A heterozygous c.773C > T transition (p.S258F) in the gap junction protein alpha 8 gene ( GJA8 ), encoding connexin 50 (Cx50), was identified in a family with congenital nuclear cataract. Functional analysis of this variant and two other GJA8 variants with unclear pathogenic mechanisms showed that the Cx50V44M mutant correctly trafficked to the plasma membrane, whereas the Cx50R76C mutant and Cx50S258F mutant exhibited trafficking defects resulting from delayed degradation and accelerated degradation, respectively. All three mutants exhibited increased autophagic activity, while only the Cx50V44M mutant and Cx50S258F mutant underwent autophagy-mediated Cx50 degradation. All mutants failed to form functional hemichannels and gap junction channels. Significance This study identified a heterozygous GJA8 missense variant c.773C > T (p.S258F) responsible for congenital nuclear cataract, and revealed three distinct pathogenic mechanisms of three cataract-associated GJA8 variants, particularly emphasizing dysregulated autophagy involving in aberrant Cx50 degradation.
研究领域:
医学遗传学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Ovarian Research
·
2024
·Vol. 17
·期 1
·1-17
·
IF 3.8
Sui Xue,Gao Bingqing,Zhang Liu,Wang Yanmin,Ma Junnan,Wu Xingchen,Zhou Chenyu,Liu Min,Zhang Lin
Background Cisplatin (DDP) is one of the most effective anticancer drugs, commonly used to treat advanced ovarian cancer (OC). However, DDP has significant limitations of platinum-based drugs, including chemical resistance and high-dose toxic side effects. Traditional Chinese medicines (TCMs) often presented in the form of formula, in which the herb pair was the basic unit. Scutellaria barbata D.Don and Hedyotis diffusa Willd (SB-HD) are famous TCMs herb pair that have been shown to help treat multiple types of cancers. However, the synergistic effects and mechanism of combination of SB-HD and DDP to enhance DDP chemosensitivity in OC are still unknown.Results In vitro, we found that the optimal proportion of SB-HD to inhibit the proliferation of OC cells was 2:1, SB-HD and DDP were shown to synergistically reduce the viability of OC cells, inhibit the colony formation, promote cell cycle arrest and apoptosis, as well as inhibit cell migration and invasion. In vivo, combination treatment significantly inhibited the growth of subcutaneous tumors in BALB/c nude mice and reduced the toxic side effects of DDP. Mechanistically, SB-HD and DDP combination treatment significantly promoted oxidative stress response, decreased MMP, inhibited ATP production, decreased ROS levels and increased SOD activity, increased the expression of NRF2, HO-1, ATG5 and LC3, decreased the expression of p62 and FTH1 both in OC cells and tumor tissue of mice. Inhibitor 3-MA (Methyladenine, autophagy inhibitor) and Fer-1 (Ferrostatin-1, iron ion inhibitor) can effectively reverse the expression changes of the key target proteins, but not ZnPP (Zinc protoporphyrin, HO-1 inhibitor). Through bioinformatics analysis, it was found that the abnormal expression level of NRF2 and FTH1 mRNA has a high prognostic value, at the same time, the other four key proteins respectively or interacting with NRF2 and FTH1, also play important roles in the occurrence and development of OC.Conclusion Our findings uncover a synergistic effect of SB-HD and DDP against OC through modulating oxidative stress via NRF2-FTH1 autophagic degradation pathway, which may provide an important theoretical foundation for the use of SB-HD and a new strategy for enhancing DDP chemosensitivity as well as reducing toxic side effects.
研究领域:
肿瘤学
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药理学
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传统中药学
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产品关联
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
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分子生物学
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细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF BIOLOGICAL CHEMISTRY
·
2025
·
IF 3.9
Qingquan Guo,Yudong Zhang,Jianhua Zhang,Xiaoyu Tian,Yawen Zhou,Yaxin Wang,Mingjie He,Lu Chen,Jiaqi Zeng,Chuanjin Tang,Qiuru Li,Zhenming He,Bingji Ma,Chenyang Jiang,Haishan Zhao
Melanin-Concentrating Hormone (MCH) is a cyclic peptide initially isolated from salmon and later found to be conserved in mammals. It plays a role in regulating melanin changes and rhythmic behaviors such as sleep and feeding, though its relationship with these processes is not fully understood. Our preliminary research revealed significant differences in melanin degradation in zebrafish under varying light conditions, suggesting a link to MCH. This study aims to explore MCH's role in lighting-induced changes in rhythmic behavior patterns and melanin of zebrafish. Using the zebrafish model, we evaluated MCH expression under different lighting conditions and analyzed the effects of arousal-promoting and sleep-inducing agents. We also investigated the impact of exogenous MCH and its inhibitors on melanin degradation, behavioral changes, and differences in MCH expression to uncover potential regulatory relationships between MCH, sleep pressure, and melanin. In-depth research using flow cytometry, AO staining, Lyso-Tracker Red staining, and RT-qPCR analysis of autophagy- and apoptosis-related genes showed that melanin degradation regulation depends on MCH expression levels. Sleep pressure can intervene in MCH's effects, forming a regulatory loop to jointly regulates melanin degradation. The influence of the MCH-sleep pressure loop on melanin degradation is closely tied to autophagic and lysosomal pathways. Our findings reveal a mutually regulatory loop in zebrafish between MCH and sleep pressure, affecting melanin degradation through these pathways.
研究领域:
神经生物学
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细胞生物学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Death & Disease
·
2023
·Vol. 14
·期 5
·1-11
·
IF 9
Cheng Jian,Zhang Guizhong,Deng Tian,Liu Zhao,Zhang Mengqi,Zhang Pengchao,Adeshakin Funmilayo O.,Niu Xiangyun,Yan Dehong,Wan Xiaochun,Yu Guang
Unbalanced protein homeostasis (proteostasis) networks are frequently linked to tumorigenesis, making cancer cells more susceptible to treatments that target proteostasis regulators. Proteasome inhibition is the first licensed proteostasis-targeting therapeutic strategy, and has been proven effective in hematological malignancy patients. However, drug resistance almost inevitably develops, pressing for a better understanding of the mechanisms that preserve proteostasis in tumor cells. Here we report that CD317, a tumor-targeting antigen with a unique topology, was upregulated in hematological malignancies and preserved proteostasis and cell viability in response to proteasome inhibitors (PIs). Knocking down CD317 lowered Ca 2+ levels in the endoplasmic reticulum (ER), promoting PIs-induced proteostasis failure and cell death. Mechanistically, CD317 interacted with calnexin (CNX), an ER chaperone protein that limits calcium refilling via the Ca 2+ pump SERCA, thereby subjecting CNX to RACK1-mediated autophagic degradation. As a result, CD317 decreased the level of CNX protein, coordinating Ca 2+ uptake and thus favoring protein folding and quality control in the ER lumen. Our findings reveal a previously unrecognized role of CD317 in proteostasis control and imply that CD317 could be a promising target for resolving PIs resistance in the clinic.
研究领域:
肿瘤学
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细胞生物学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
LIFE SCIENCES
·
2024
·
IF 5.2
Xianzhe Wang,Yanyan Zhu,Huilin Liu,Xiangchuan Wang,Hongjie Zhang,Xiuping Chen
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease characterized by irreversible lung scarring with a poor prognosis. Emerging evidence has revealed that IPF is an aging-related disease, and the development of cellular senescence plays a pivotal role in persistent remodeling and fibrotic scarring, acting as a key mechanism in the pathophysiology of IPF. Exploring therapeutic strategies for modulating cellular senescence can provide crucial insights into unraveling IPF processes. Here, we have identified Nitazoxanide (NTZ), an FDA-approved antiprotozoal agent, has specific effects on inhibiting cellular senescence development. In the bleomycin and D-galactose-induced senescence model, NTZ effectively inhibits senescence associated-β-gal staining and preserves cell proliferation ability. We also found that NTZ effectively impedes senescence progression in the bleomycin-induced pulmonary fibrosis model, while mitigating the release of senescence-associated secretory phenotype and alleviating pulmonary fibrosis. The anti-senescence effect of NTZ is mechanistically dependent on the preservation of nuclear SIRT1 expression. We observed that PI3K induces a WIPI1-mediated nucleophagic degradation of SIRT1, while NTZ effectively inhibits PI3K and suppresses WIPI1 expression, thereby maintaining SIRT1 expression in the nucleus and exerting its anti-senescence function. Collectively, our research has shown that NTZ can inhibit PI3K in senescence progression, leading to the inhibition of WIPI1-mediated SIRT1 nucleophagic degradation. As a result, NTZ alleviates fibrosis by inhibiting senescence development.
研究领域:
药理学
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肺科学
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细胞生物学
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衰老研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CELL DEATH AND DIFFERENTIATION
·
2025
·
IF 15.4
Zeng Ke,Zhu Yuqi,Han Zhongxin,Xiong Siyi,Zhao Yan,Xiao Zilong,Xie Yingchao,Jin Shiyu,Dong Tingru,Lan Lan,Liu Weiwei,Du Yongzhong,Guan Cuiping,Yu Xiao,Song Xiuzu
NLRP3 functions as a critical intracellular danger sensor for inflammasome activation, playing a crucial role in autoimmune diseases. Vitiligo progression has been linked to NLRP3, yet its specific involvement in melanocytes of vitiligo remains poorly understood. In this study, we demonstrate that NLRP3 expression is significantly upregulated in the melanocytes of vitiligo patients and melanoma-Treg-induced vitiligo mouse model. Genetic knockout of NLRP3 effectively alleviates vitiligo progression in these mice. Our mechanistic investigations reveal that the downregulation of the E3 ligase β-TrCP1 in vitiligo melanocytes decreases K27-linked ubiquitination levels of NLRP3, which in turn weakens its interaction with the autophagy receptor NDP52. This disruption impairs the selective autophagic degradation of NLRP3, leading to hyperactivation of inflammation and pyroptosis in melanocytes, thereby accelerating vitiligo pathogenesis. Notably, melanocyte-specific knockdown of NLRP3 using lysine-proline-valine (KPV)-modified deformable liposomes (KPV-Lipos) carrying Nlrp3 shRNA significantly alleviates vitiligo development. This study elucidates the mechanism by which autophagy dysfunction mediated excessive NLRP3 inflammasome activation in melanocytes contributes to vitiligo pathogenesis, highlighting potential therapeutic strategies targeting these pathways for the treatment of vitiligo and other pigment-related skin diseases. Overview of disrupted NLRP3 autophagic degradation in vitiligo melanocytes . In healthy melanocytes, NLRP3 expression is upregulated when subjected to oxidative stress, along with an increase in the E3 ligase β-TrCP1, which enhances the K27-linked ubiquitination of NLRP3 and further strengthens its binding to the autophagy receptor protein NDP52, thus effectively suppressing the excessive inflammatory response. Whereas in the melanocytes of vitiligo patients, decreased expression of β-TrCP1 leads to downregulation of K27-linked ubiquitination in NLRP3, thus inhibiting its autophagic degradation. The persistent activation of NLRP3 in vitiligo melanocytes promotes the cleavage of pro-IL-1β and GSDMD. GSDMD-N subsequently forms pores on the cell membrane, which causes the release of IL-1β and results in melanocyte pyroptosis. In our study, we utilize KPV-Lipos with Nlrp3 shRNA to precisely knockdown NLRP3 expression in melanocytes and effectively alleviate vitiligo development, which provide a potentially promising strategy for the treatment of vitiligo. MC, melanocytes.
研究领域:
皮肤病学
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免疫学
·
细胞生物学
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自身免疫性疾病
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2024
·
IF 14.3
Jingxuan Cui,Yujia Chen,Qiannan Yang,Peng Zhao,Mian Yang,Xiaoqi Wang,Ge Mang,Xiangyu Yan,Di Wang,Zhonghua Tong,Penghe Wang,Yingjin Kong,Naixin Wang,Dongni Wang,Nana Dong,Mingyang Liu,Mingyan E,Maomao Zhang,Bo Yu
Doxorubicin (DOX) is an effective anticancer agent, but its clinical utility is constrained by dose-dependent cardiotoxicity, partly due to cardiomyocyte ferroptosis. However, the progress of developing cardioprotective medications to counteract ferroptosis has encountered obstacles. Protosappanin A (PrA), an anti-inflammatory compound derived from hematoxylin, shows potential against DOX-induced cardiomyopathy (DIC). Here, it is reported that PrA alleviates myocardial damage and dysfunction by reducing DOX-induced ferroptosis and maintaining mitochondrial homeostasis. Subsequently, the molecular target of PrA through proteome microarray, molecular docking, and dynamics simulation is identified. Mechanistically, PrA physically binds with ferroptosis-related proteins acyl-CoA synthetase long-chain family member 4 (ACSL4) and ferritin heavy chain 1 (FTH1), ultimately inhibiting ACSL4 phosphorylation and subsequent phospholipid peroxidation, while also preventing FTH1 autophagic degradation and subsequent release of ferrous ions (Fe 2+ ) release. Given the critical role of ferroptosis in the pathogenesis of ischemia-reperfusion (IR) injury, this further investigation posits that PrA can confer a protective effect against IR-induced cardiac damage by inhibiting ferroptosis. Overall, a novel pharmacological inhibitor is unveiled that targets ferroptosis and uncover a dual-regulated mechanism for cardiomyocyte ferroptosis in DIC, highlighting additional therapeutic options for chemodrug-induced cardiotoxicity and ferroptosis-triggered disorders.
研究领域:
药理学
·
心脏病学
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肿瘤学
·
分子生物学
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生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Death & Disease
·
2023
·Vol. 14
·期 10
·1-17
·
IF 9
Deng Huan,Chen Yamei,Wang Li,Zhang Yibi,Hang Qingqing,Li Peijing,Zhang Peng,Ji Jing,Song Hai,Chen Ming,Jin Ying
Our previous study revealed that PI3K/AKT/mTOR signaling was associated with SCLC radioresistance. SBC2 cells were used as primary radioresistance models, while H446 cells were continuously exposed to ionizing radiation (IR) to develop acquired radioresistance. Cell viability and apoptosis assays were used to investigate synergistic effects of BEZ235/GSK2126458 and IR in vitro, while immunoblotting, metabolite quantitative analysis and bioinformatic analyses were utilized to explore the underlying mechanism. Both genetically engineered mouse models (GEMM) and subcutaneous tumor models were used to confirm the synergistic effect in vivo. Key molecules of PI3K/AKT/mTOR signaling were upregulated after IR, which was correlated with primary radioresistance, and they were more expressed in acquired radioresistant cells. BEZ235/GSK2126458 effectively enhanced the cytotoxic effects of IR. BEZ235/GSK2126458 plus IR elevated γ-H2AX and p-Nrf2 expression, suggesting DNA and oxidative stress damage were intensified. Mechanistically, BEZ235/GSK2126458 plus IR significantly reduced the expression of G6PD protein, the rate-limiting enzyme of the pentose phosphate pathway (PPP). In detail, PI3K/mTOR inhibitors reinforced interaction between G6PD and HSPA8/HSC70, and G6PD was degraded by chaperone-mediated autophagy processes. Their metabolites (NADPH and R-5P) were decreased, and ROS levels were indirectly elevated, both of which exacerbated cell death. PI3K/AKT/mTOR signaling activator, insulin, enhanced SCLC radioresistance, while the synergistic effect of BEZ235/GSK2126458 and IR can be attenuated by N-acetylcysteine, and enhanced by 6-amino niacinamide. GEMM and allograft transplantation assays further confirmed their synergistic effect in vivo. This study provided insights into the connection between PI3K/AKT/mTOR signaling and the PPP underlying radioresistance and provided evidence of mechanisms supporting PI3K/mTOR inhibitors as possible therapeutic strategies to abrogate SCLC radioresistance.
研究领域:
肿瘤学
·
药理学
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细胞生物学
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分子生物学
·
放射生物学
✓ 已验证
DOI
PubMed
高影响因子
Cell Reports
·
2023
·
IF 8.8
Yingqi Liu,Xuemei Yao,Youbo Zhao,De Fang,Lei Shi,Li Yang,Guanbin Song,Kaiyong Cai,Liqi Li,Qin Deng,Menghuan Li,Zhong Luo
The tumor microenvironment (TME) plays decisive roles in disabling T cell-mediated antitumor immunity, but the immunoregulatory functions of its biophysical properties remain elusive. Extracellular matrix (ECM) stiffening is a hallmark of solid tumors. Here, we report that the stiffened ECM contributes to the immunosuppression in TME via activating the Rho-associated coiled-coil-containing protein kinase (ROCK)-myosin IIA-filamentous actin (F-actin) mechanosignaling pathway in tumor cells to promote the generation of TRIM14-scavenging nonmuscle myosin heavy chain IIA (NMHC-IIA)-F-actin stress fibers, thus accelerating the autophagic degradation of cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) to deprive tumor cyclic GMP-AMP (cGAMP) and further attenuating tumor immunogenicity. Pharmacological inhibition of myosin IIA effector molecules with blebbistatin (BLEB) or the RhoA upstream regulator of this pathway with simvastatin (SIM) restored tumor-intrinsic cGAS-mediated cGAMP production and enhanced antitumor immunity. Our work identifies that ECM stiffness is an important biophysical cue to regulate tumor immunogenicity via the ROCK-myosin IIA-F-actin axis and that inhibiting this mechanosignaling pathway could boost immunotherapeutic efficacy for effective solid tumor treatment.
研究领域:
癌症生物学
·
免疫学
·
细胞生物学
·
生物物理学
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）