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The Mycobacterium tuberculosis lipid, PDIM, inhibits the NADPH oxidase and autophagy. 结核分枝杆菌脂质,PDIM,抑制NADPH氧化酶和自噬。
Pub Date : 2025-03-01 Epub Date: 2024-12-15 DOI: 10.1080/15548627.2024.2439928
Ekansh Mittal, Jennifer A Philips

Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis (TB), remains a significant global health challenge. Mtb is transmitted by respiratory aerosols and infects a variety of myeloid populations. Our recent study shows that the Mtb virulence lipid phthiocerol dimycocerosate (PDIM) promotes the intracellular survival of Mtb in macrophages by inhibiting NADPH oxidase, thereby impairing LC3-associated phagocytosis, and in vivo PDIM also antagonizes canonical macroautophagy/autophagy. In addition, mice defective in autophagy in myeloid cells fail to develop B-cell follicles in the lungs during chronic infection. Here, we present a summary of our recent publication, highlighting the most significant findings and discussing how they provide new insight into the role of autophagy and the diversity of lung myeloid cells in the pathogenesis of Mtb.

结核分枝杆菌(Mtb),结核病(TB)的病原,仍然是一个重大的全球卫生挑战。结核分枝杆菌通过呼吸道气溶胶传播,感染多种髓系人群。我们最近的研究表明,Mtb毒力脂质邻硫酚二真菌酸酯(PDIM)通过抑制NADPH氧化酶促进巨噬细胞内Mtb的存活,从而损害lc3相关的吞噬作用,并且在体内PDIM还能拮抗典型巨噬/自噬。此外,在慢性感染期间,骨髓细胞自噬缺陷的小鼠不能在肺部发育b细胞滤泡。在这里,我们总结了我们最近发表的文章,突出了最重要的发现,并讨论了它们如何为自噬和肺髓细胞多样性在结核分枝杆菌发病机制中的作用提供了新的见解。
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引用次数: 0
Correction. 修正。
Pub Date : 2025-03-01 Epub Date: 2025-01-15 DOI: 10.1080/15548627.2024.2431342
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引用次数: 0
Copper aggravated synaptic damage after traumatic brain injury by downregulating BNIP3-mediated mitophagy. 铜通过下调 BNIP3 介导的有丝分裂,加剧了创伤性脑损伤后的突触损伤。
Pub Date : 2025-03-01 Epub Date: 2024-10-16 DOI: 10.1080/15548627.2024.2409613
Hanxiao Chang, Weiwei Zhang, Lei Xu, Zheng Li, Chao Lin, Yuqi Shen, Guangjian Zhang, Lei Mao, Chencheng Ma, Ning Liu, Hua Lu

Synaptic damage is a crucial pathological process in traumatic brain injury. However, the mechanisms driving this process remain poorly understood. In this report, we demonstrate that the accumulation of damaged mitochondria, resulting from impaired mitphagy, plays a significant role in causing synaptic damage. Moreover, copper induced downregulation of BNIP3 is a key player in regulating mitophagy. DMSA alleviates synaptic damage and mitochondrial dysfunction by promoting urinary excretion of copper. Mechanistically, we find that copper downregulate BNIP3 by increasing the nuclear translocation of NFKB, which is triggered by TRIM25-mediated ubiquitination-dependent degradation of NFKBIA. Our study underscores the importance of copper accumulation in the regulation of BNIP3-mediated mitophagy and suggests that therapeutic targeting of the copper-TRIM25-NFKB-BNIP3 axis holds promise to attenuate synaptic damage after traumatic brain injury.

突触损伤是创伤性脑损伤的一个重要病理过程。然而,人们对这一过程的驱动机制仍然知之甚少。在本报告中,我们证明了有丝分裂障碍导致的受损线粒体积累在造成突触损伤中起着重要作用。此外,铜诱导的 BNIP3 下调是调节有丝分裂的关键因素。DMSA 可通过促进尿液中铜的排泄来缓解突触损伤和线粒体功能障碍。从机理上讲,我们发现铜通过增加 NFKB 的核转位来下调 BNIP3,而 NFKB 的核转位是由 TRIM25 介导的 NFKBIA 泛素化依赖性降解触发的。我们的研究强调了铜积累在调控 BNIP3 介导的有丝分裂中的重要性,并表明针对铜-TRIM25-NFKB-BNIP3 轴的治疗有望减轻创伤性脑损伤后的突触损伤。
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引用次数: 0
SMURF1 mediates damaged lysosomal homeostasis by ubiquitinating PPP3CB to promote the activation of TFEB. SMURF1 通过泛素化 PPP3CB 来促进 TFEB 的活化,从而介导受损溶酶体的稳态。
Pub Date : 2025-03-01 Epub Date: 2024-10-14 DOI: 10.1080/15548627.2024.2407709
Qin Xia, Xuan Liu, Lu Zhong, Jun Qu, Lei Dong

The calcium-activated phosphatase PPP3/calcineurin dephosphorylates TFEB (transcription factor EB) to trigger its nuclear translocation and the activation of macroautophagic/autophagic targets. However, the detailed molecular mechanism regulating TFEB activation remains poorly understood. Here, we highlighted the importance of SMURF1 (SMAD specific E3 ubiquitin protein ligase 1) in the activation of TFEB for lysosomal homeostasis. SMURF1 deficiency prevents the calcium-triggered ubiquitination of the catalytic subunit of PPP3/calcineurin in a manner consistent with defective autophagic degradation of damaged lysosomes. Mechanically, PPP3CB/CNA2 plays a bridging role in the recruitment of SMURF1 by LGALS3 (galectin 3) upon lysosome damage. Importantly, PPP3CB increases the dissociation of the N-terminal tail (NT) and C-terminal carbohydrate-recognition domain (CRD) of LGALS3, which may promote the formation of open conformers in a PPP3CB dephosphorylation activity-dependent manner. In addition, PPP3CB is ubiquitinated at lysine 146 by the recruited SMURF1 in response to intracellular calcium stimulation. The K63-linked ubiquitination of PPP3CB enhances the recruitment of TFEB. Moreover, TFEB directly interacts with both PPP3CB and the regulatory subunit PPP3R1 which facilitate the conformational correction of TFEB for its activation for the transcription of TFEB-targeted genes. Altogether, our results highlighted a critical mechanism for the regulation of PPP3/calcineurin activity via its ubiquitin ligase SMURF1 in response to lysosomal membrane damage, which may account for a potential target for the treatment of stress-related diseases.Abbreviation AID: autoinhibitory domain; ATG: autophagy related; CD: catalytic domain; CRD: carbohydrate-recognition domain; CsA: cyclosporin A; DMSO: dimethyl sulfoxide; ESCRT: endosomal sorting complexes required for transport; GSK3B: glycogen synthase kinase 3 beta; LAMP1: lysosomal associated membrane protein 1; LGALS3: galectin 3; LLOMe: L-leucyl-L-leucine methyl ester; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; ML-SA1: mucolipin synthetic agonist 1; MTORC1: mechanistic target of rapamycin kinase complex 1; NT: N-terminal tail; PPP3CB: protein phosphatase 3 catalytic subunit beta; PPP3R1: protein phosphatase 3 regulatory subunit B, alpha; SMURF1: SMAD specific E3 ubiquitin protein ligase 1; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB; VCP/p97: valosin containing protein; YWHA/14-3-3: tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein.

钙激活磷酸酶 PPP3/calcineurin 可使 TFEB(转录因子 EB)去磷酸化,从而引发其核转位并激活大自噬/自噬靶标。然而,调控 TFEB 激活的详细分子机制仍鲜为人知。在这里,我们强调了SMURF1(SMAD特异性E3泛素蛋白连接酶1)在激活TFEB促进溶酶体稳态中的重要性。SMURF1 缺乏会阻止钙触发的 PPP3/calcineurin 催化亚基泛素化,其方式与受损溶酶体的自噬降解缺陷一致。从机理上讲,PPP3CB/CNA2 在溶酶体损伤后 LGALS3(galectin 3)招募 SMURF1 的过程中起着桥接作用。重要的是,PPP3CB 增加了 LGALS3 的 N 端尾(NT)和 C 端碳水化合物识别域(CRD)的解离,这可能会以 PPP3CB 去磷酸化活性依赖的方式促进开放构象的形成。此外,PPP3CB 在赖氨酸 146 处被招募的 SMURF1 泛素化,以响应细胞内的钙刺激。PPP3CB 的 K63 链接泛素化增强了 TFEB 的招募。此外,TFEB 直接与 PPP3CB 和调控亚基 PPP3R1 相互作用,从而促进 TFEB 的构象校正,以激活 TFEB 靶向基因的转录。总之,我们的研究结果突显了溶酶体膜损伤时通过泛素连接酶 SMURF1 调节 PPP3/calcineurin 活性的关键机制,这可能是治疗应激相关疾病的潜在靶点。
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引用次数: 0
A novel ER stress regulator ARL6IP5 induces reticulophagy to ameliorate the prion burden. 新型ER应激调节因子ARL6IP5可诱导网状吞噬作用,从而减轻朊病毒的负担。
Pub Date : 2025-03-01 Epub Date: 2024-10-24 DOI: 10.1080/15548627.2024.2410670
Kajal Kamble, Ujjwal Kumar, Harsh Aahra, Mohit Yadav, Sumnil Bhola, Sarika Gupta

Prion disease is a fatal and infectious neurodegenerative disorder caused by the trans-conformation conversion of PRNP/PrPC to PRNP/PrPSc. Accumulated PRNP/PrPSc-induced ER stress causes chronic unfolded protein response (UPR) activation, which is one of the fundamental steps in prion disease progression. However, the role of various ER-resident proteins in prion-induced ER stress is elusive. This study demonstrated that ARL6IP5 is compensatory upregulated in response to chronically activated UPR in the cellular prion disease model (RML-ScN2a). Furthermore, overexpression of ARL6IP5 overcomes ER stress by lowering the expression of chronically activated UPR pathway proteins. We discovered that ARL6IP5 induces reticulophagy to reduce the PRNP/PrPSc burden by releasing ER stress. Conversely, the knockdown of ARL6IP5 leads to inefficient macroautophagic/autophagic flux and elevated PRNP/PrPSc burden. Our study also uncovered that ARL6IP5-induced reticulophagy depends on Ca2+-mediated AMPK activation and can induce 3 MA-inhibited autophagic flux. The detailed mechanistic study revealed that ARL6IP5-induced reticulophagy involves interaction with soluble reticulophagy receptor CALCOCO1 and lysosomal marker LAMP1, leading to degradation in lysosomes. Here, we delineate the role of ARL6IP5 as a novel ER stress regulator and reticulophagy inducer that can effectively reduce the misfolded PRNP/PrPSc burden. Our research opens up a new avenue of selective autophagy in prion disease and represents a potential therapeutic target.Abbreviations: ARL6IP5: ADP ribosylation factor-like GTPase 6 interacting protein 5; AMPK: adenosine 5'-monophosphate (AMP)-activated protein kinase; CALCOCO1: calcium binding and coiled-coil domain 1; CQ: chloroquine; DAPI: 4'6-diamino-2-phenylindole; ER: endoplasmic reticulum; ERPHS: reticulophagy/ER-phagy sites; KD: knockdown; KD-CON: knockdown control; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3/LC3, microtubule-associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; MβCD: methyl beta cyclodextrin; 3 MA: 3-methyladenine; OE: overexpression; OE-CON: empty vector control; PrDs: prion diseases; PRNP/PrPC: cellular prion protein (Kanno blood group); PRNP/PrPSc: infectious scrapie misfolded PRNP; Tm: tunicamycin; UPR: unfolded protein response; UPS: ubiquitin-proteasome system.

朊病毒病是一种致命的传染性神经退行性疾病,由 PRNP/PrPC 向 PRNP/PrPSc 的反式转化引起。累积的 PRNP/PrPSc 诱导的ER应激导致慢性未折叠蛋白反应(UPR)激活,这是朊病毒病进展的基本步骤之一。然而,各种ER驻留蛋白在朊病毒诱导的ER应激中的作用尚不明确。本研究表明,在细胞朊病毒疾病模型(RML-ScN2a)中,ARL6IP5在慢性激活的UPR作用下呈代偿性上调。此外,过表达 ARL6IP5 可降低慢性激活的 UPR 通路蛋白的表达,从而克服 ER 应激。我们发现,ARL6IP5能通过释放ER压力诱导网状吞噬作用,从而减轻PRNP/PrPSc的负担。相反,敲除 ARL6IP5 会导致大自噬/自噬通量效率低下和 PRNP/PrPSc 负担升高。我们的研究还发现,ARL6IP5 诱导的网吞噬依赖于 Ca2+ 介导的 AMPK 激活,并能诱导 3 MA 抑制的自噬通量。详细的机理研究显示,ARL6IP5诱导的网吞噬涉及与可溶性网吞噬受体CALCOCO1和溶酶体标志物LAMP1的相互作用,导致其在溶酶体中降解。在这里,我们描述了 ARL6IP5 作为一种新型 ER 应激调节剂和网吞噬诱导剂的作用,它能有效减少错误折叠的 PRNP/PrPSc 负担。我们的研究为朊病毒疾病中的选择性自噬开辟了一条新途径,并代表了一种潜在的治疗靶点。
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引用次数: 0
Empagliflozin protects the kidney by reducing toxic ALB (albumin) exposure and preventing autophagic stagnation in proximal tubules. Empagliflozin 可减少有毒 ALB(白蛋白)的暴露,防止近端肾小管自噬停滞,从而保护肾脏。
Pub Date : 2025-03-01 Epub Date: 2024-10-14 DOI: 10.1080/15548627.2024.2410621
Sho Matsui, Takeshi Yamamoto, Yoshitsugu Takabatake, Atsushi Takahashi, Tomoko Namba-Hamano, Jun Matsuda, Satoshi Minami, Shinsuke Sakai, Hiroaki Yonishi, Jun Nakamura, Shihomi Maeda, Ayumi Matsumoto, Isao Matsui, Motoko Yanagita, Yoshitaka Isaka

The renoprotective effects of SLC5A2/SGLT2 (solute carrier 5 (sodium/glucose cotransporter), member 2) inhibitors have recently been demonstrated in non-diabetic chronic kidney disease (CKD), even without overt albuminuria. However, the mechanism underlying this renoprotection is largely unclear. We investigated the renoprotective mechanisms of the SLC5A2 inhibitor empagliflozin with a focus on ALB (albumin) reabsorption and macroautophagy/autophagy in proximal tubules using wild-type or drug-inducible lrp2/Megalin or atg5 knockout mice with high-fat diet (HFD)-induced obesity or 5/6 nephrectomy that elevated intraglomerular pressure without overt albuminuria. Empagliflozin treatment of HFD-fed mice reduced several hallmarks of lipotoxicity in the proximal tubules, such as phospholipid accumulation in the lysosome, inflammation and fibrosis. Empagliflozin, which decreases intraglomerular pressure, not only reduced the HFD-induced increase in ALB reabsorption via LRP2 in the proximal tubules (i.e. total nephron ALB filtration), as assessed by urinary ALB excretion caused by genetic ablation of Lrp2, but also ameliorated the HFD-induced imbalance in circulating ALB-bound fatty acids. Empagliflozin alleviated the HFD-induced increase in autophagic demand and successfully prevented autophagic stagnation in the proximal tubules. Similarly, empagliflozin decreased ALB exposure and autophagic demand in 5/6 nephrectomized mice. Finally, empagliflozin reduced HFD-induced vulnerability to ischemia-reperfusion injury, whereas LRP2 blockade and atg5 ablation separately diminished this effect. Our findings indicate that empagliflozin reduces ALB exposure and prevents autophagic stagnation in the proximal tubules even without overt albuminuria. Autophagy improvement may be critical for the renoprotection mediated by SLC5A2 inhibition.

最近,SLC5A2/SGLT2(溶质运载体 5(钠/葡萄糖共转运体),成员 2)抑制剂对非糖尿病慢性肾病(CKD)的肾脏保护作用已得到证实,即使没有明显的白蛋白尿。然而,这种肾保护作用的机制尚不清楚。我们使用野生型或药物诱导的 lrp2/Megalin 或 atg5 基因敲除小鼠,研究了 SLC5A2 抑制剂 Empagliflozin 的肾脏保护机制,重点是 ALB(白蛋白)重吸收和近端肾小管的大自噬/自噬,这些小鼠由高脂饮食(HFD)诱导肥胖或 5/6 肾切除术导致肾小球内压升高,但没有明显的白蛋白尿。用 Empagliflozin 治疗高脂饮食喂养的小鼠可减少近端肾小管脂肪毒性的几个特征,如溶酶体中磷脂的积累、炎症和纤维化。Empagliflozin 能降低肾小球内压,它不仅能降低高氟酸膳食诱导的近端肾小管通过 LRP2 重吸收 ALB 的增加(即肾小球 ALB 总滤过量)(由遗传性 Lrp2 消减引起的尿 ALB 排泄评估),还能改善高氟酸膳食诱导的循环 ALB 结合脂肪酸的不平衡。Empagliflozin 可缓解 HFD 诱导的自噬需求增加,并成功地防止了近端肾小管的自噬停滞。同样,在 5/6 肾切除的小鼠中,empagliflozin 也能减少 ALB 暴露和自噬需求。最后,empagliflozin 降低了高密度脂蛋白胆固醇诱导的缺血再灌注损伤的易感性,而 LRP2 阻断和 atg5 消融则分别减弱了这种效应。我们的研究结果表明,即使没有明显的白蛋白尿,empagliflozin 也能减少 ALB 暴露并防止近端肾小管的自噬停滞。自噬的改善可能是 SLC5A2 抑制介导的肾脏保护的关键。
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引用次数: 0
USP13 facilitates a ferroptosis-to-autophagy switch by activation of the NFE2L2/NRF2-SQSTM1/p62-KEAP1 axis dependent on the KRAS signaling pathway. USP13 通过激活依赖于 KRAS 信号通路的 NFE2L2/NRF2-SQSTM1/p62-KEAP1 轴,促进铁变态反应向自噬的转换。
Pub Date : 2025-03-01 Epub Date: 2024-10-10 DOI: 10.1080/15548627.2024.2410619
Ling Chen, Jieling Ning, Li Linghu, Jun Tang, Na Liu, Yao Long, Jingyue Sun, Cairui Lv, Ying Shi, Tania Tao, Desheng Xiao, Ya Cao, Xiang Wang, Shuang Liu, Guangjian Li, Bin Zhang, Yongguang Tao

Macroautophagy/autophagyis a lysosomal-regulated degradation process that participates incellular stress and then promotes cell survival or triggers celldeath. Ferroptosis was initially described as anautophagy-independent, iron-regulated, nonapoptotic cell death.However, recent studies have revealed that autophagy is positivelyassociated with sensitivity to ferroptosis. Nonetheless, themolecular mechanisms by which these two types of regulated cell death(RCD) modulate each other remain largely unclear. Here, we screened85 deubiquitinating enzymes (DUBs) and found that overexpression ofUSP13 (ubiquitin specific peptidase 13) could significantlyupregulate NFE2L2/NRF2 (NFE2 like bZIP transcription factor 2)protein levels. In addition, in 39 cases of KRAS-mutated lungadenocarcinoma (LUAD), we found that approximately 76% of USP13overexpression is positively correlated with NFE2L2 overexpression.USP13 interacts with and catalyzes the deubiquitination of thetranscription factor NFE2L2. Additionally, USP13 depletion promotesan autophagy-to-ferroptosis switch invitro andin xenograft tumor mouse models, through the activation of theNFE2L2-SQSTM1/p62 (sequestosome 1)-KEAP1 axis in KRAS mutant cellsand tumor tissues. Hence, targeting USP13 effectively switchedautophagy-to-ferroptosis, thereby inhibiting KRAS (KRASproto-oncogene, GTPase) mutant LUAD, suggesting the therapeuticpromise of combining autophagy and ferroptosis in the KRAS-mutantLUAD.Abbreviation: ACSL4: acyl-CoA synthetase long-chain family member 4; ACTB: actin beta; AL: autolysosomes; AP: autophagosomes; BCL2L1/BCL-xL: BCL2 like 1; CCK8: Cell Counting Kit-8; CQ: chloroquine; CUL3: cullin 3; DMSO: dimethyl sulfoxide; DOX: doxorubicin; DUB: deubiquitinating enzyme; Ferr-1: ferrostatin-1; GPX4: glutathione peroxidase 4; GSEA: gene set enrichment analysis; 4HNE: 4-hydroxynonenal; IKE: imidazole ketone erastin; KEAP1: kelch like ECH associated protein 1; KRAS: KRAS proto-oncogene, GTPase; LCSC: lung squamous cell carcinoma; IF: immunofluorescence; LUAD: lung adenocarcinoma; Lys05: Lys01 trihydrochloride; MAPK1/ERK2/p42: mitogen-activated protein kinase 1; MAPK3/ERK1/p44; MTOR: mechanistic target of rapamycin kinase; NFE2L2/NRF2: NFE2 like bZIP transcription factor, 2; NQO1: NAD(P)H quinone dehydrogenase 1; PG: phagophore; RCD: regulated cell death; RAPA: rapamycin; ROS: reactive oxygen species; SLC7A11/xCT: solute carrier family 7 member 11; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; TUBB/beta-tubulin: tubulin, beta; UPS: ubiquitin-proteasome system; USP13: ubiquitin specific peptidase 13.

大自噬/自噬是一种溶酶体调控的降解过程,它参与细胞应激,然后促进细胞存活或引发细胞死亡。然而,最近的研究发现,自噬与对铁变态反应的敏感性呈正相关。然而,这两种调控细胞死亡(RCD)相互调节的分子机制在很大程度上仍不清楚。在此,我们筛选了85种去泛素化酶(DUBs),发现过表达USP13(泛素特异性肽酶13)可显著调节NFE2L2/NRF2(NFE2 like bZIP transcription factor 2)蛋白水平。此外,在 39 例 KRAS 突变的肺腺癌(LUAD)中,我们发现约 76% 的 USP13 表达与 NFE2L2 的过表达呈正相关。此外,通过激活 KRAS 突变细胞和肿瘤组织中的 NFE2L2-SQSTM1/p62(sequestosome 1)-KEAP1 轴,USP13 的耗竭可在体外和异种移植肿瘤小鼠模型中促进自噬到铁蛋白沉积的转换。因此,靶向 USP13 能有效地将自噬转为铁变态反应,从而抑制 KRAS(KRAS 原癌基因,GTPase)突变型 LUAD,这表明在 KRAS 突变型 LUAD 中结合自噬和铁变态反应具有治疗前景。
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引用次数: 0
Autophagy as a way to remove DNA lesions. 自噬是一种清除DNA损伤的方法。
Pub Date : 2025-03-01 Epub Date: 2024-12-15 DOI: 10.1080/15548627.2024.2434784
Yuchen Lei, Daniel J Klionsky

Type I topoisomerases (TOP1) are critical to remove the topological stress when DNA double strands are unwound. The TOP1 cleavage complexes (TOP1cc) are normally transient, and the stabilization of TOP1cc by its inhibitors, such as camptothecin (CPT), may lead to DNA damage and become cytotoxic. The proteasome pathway degrades trapped TOP1, which is necessary for the repair machinery to gain access to the DNA; however, this process is mainly described when the CPT concentration is high, at levels which are clinically unachievable. In a recently published study, Lascaux et al. identify macroautophagy/autophagy as a new pathway to remove DNA lesions upon clinically relevant low-dose CPT treatment. The autophagy receptor TEX264 binds to TOP1 and brings this protein and its bound DNA fragments to the phagophore; subsequently, they are ultimately delivered to the lysosome for degradation. This study demonstrates the role of autophagy in maintaining genome stability from a new perspective and reveals potential targets to deal with the resistance to TOP1cc inhibitors during cancer treatment.

I型拓扑异构酶(TOP1)是消除DNA双链解绕时拓扑应力的关键。TOP1切割复合物(TOP1cc)通常是短暂的,其抑制剂如喜树碱(CPT)对TOP1cc的稳定可能导致DNA损伤并具有细胞毒性。蛋白酶体途径降解捕获的TOP1,这是修复机制进入DNA所必需的;然而,这一过程主要发生在CPT浓度很高的情况下,达到临床无法达到的水平。在最近发表的一项研究中,Lascaux等人发现巨噬/自噬是通过临床相关的低剂量CPT治疗去除DNA病变的新途径。自噬受体TEX264与TOP1结合,并将该蛋白及其结合的DNA片段带到吞噬细胞;随后,它们最终被送到溶酶体降解。本研究从一个新的角度论证了自噬在维持基因组稳定性中的作用,并揭示了在癌症治疗过程中处理对TOP1cc抑制剂耐药的潜在靶点。
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引用次数: 0
HSP90 N-terminal inhibition promotes mitochondria-derived vesicles related metastasis by reducing TFEB transcription via decreased HSP90AA1-HCFC1 interaction in liver cancer. 在肝癌中,HSP90 N-端抑制通过减少HSP90AA1与HCFC1的相互作用,降低TFEB转录,从而促进线粒体衍生囊泡的相关转移。
Pub Date : 2025-03-01 Epub Date: 2024-11-11 DOI: 10.1080/15548627.2024.2421703
Lixia Liu, Zhenming Zheng, Yaling Huang, Hairou Su, Guibing Wu, Zihao Deng, Yan Li, Guantai Xie, Jieyou Li, Fei Zou, Xuemei Chen

Cancer cells compensate with increasing mitochondria-derived vesicles (MDVs) to maintain mitochondrial homeostasis, when canonical MAP1LC3B/LC3B (microtubule associated protein 1 light chain 3 beta)-mediated mitophagy is lacking. MDVs promote the transport of mitochondrial components into extracellular vesicles (EVs) and induce tumor metastasis. Although HSP90 (heat shock protein 90) chaperones hundreds of client proteins and its inhibitors suppress tumors, HSP90 inhibitors-related chemotherapy is associated with unexpected metastasis. Herein, we find that HSP90 inhibitor causes mitochondrial damage but stimulates the low LC3-induced MDVs and the release of MDVs-derived EVs. However, why LC3 decreases and what is the transcriptional regulatory mechanism of MDVs formation under HSP90 inhibition remain unknown. Because TFEB (transcription factor EB) is the most important mitophagy transcription factor, and the HSP90 client HCFC1 (host cell factor C1) regulates TFEB transcription, there should be a hidden connection between TFEB, HCFC1 and HSP90 in MDVs formation. Our results support the idea that HSP90 N-terminal inhibition reduces TFEB transcription via decreased HSP90AA1-HCFC1 interaction, which prevents HCFC1 from binding to the TFEB proximal promoter region. Decreased TFEB transcription and consequently reduced LC3, ultimately promoted MDVs formation. Blocking MDVs formation with the microtubule inhibitor nocodazole (NOC) activates the HCFC1-TFEB-LC3 axis, weakens HSP90 inhibitors-induced MDVs and the release of MDVs-derived EVs, inhibits the growth of tumor cell spheres and primary liver tumors, and reduces the extravasation of cancer cells to secondary metastatic sites. Taken together, these data suggest that combination therapy should be used to reduce the metastatic risk of low TFEB-triggered-MDVs formation caused by HSP90 inhibitors.Abbreviation: ACIs: ATP-competitive inhibitors; BaFA1: bafilomycin A1; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; ChIP: chromatin immunoprecipitation; CHX: cycloheximide; CTD: C-terminal domain; EVs: extracellular vesicles; HCFC1: host cell factor C1; HSP90: heat shock protein 90; ILVs: intralumenal vesicles; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MD: middle domain; MDVs: mitochondria-derived vesicles; MQC: mitochondrial quality control; ΔΨm: mitochondrial membrane potential; MVBs: multivesicular bodies; NB: novobiocin; TEM: transmission electron microscopy; TFEB: transcription factor EB; TFs: transcription factors. NOC: nocodazole; NTD: N-terminal nucleotide binding domain; OCR: oxygen consumption rate; RFP: red fluorescent protein; ROS: reactive oxygen species; STA9090: Ganetespib; VPS35: VPS35 retromer complex component.

当缺乏典型的 MAP1LC3B/LC3B(微管相关蛋白 1 轻链 3 beta)介导的有丝分裂时,癌细胞会通过增加线粒体衍生囊泡(MDVs)来维持线粒体的平衡。MDV 促进线粒体成分向细胞外囊泡 (EV) 的运输,并诱发肿瘤转移。虽然 HSP90(热休克蛋白 90)能合成数百种客户蛋白,其抑制剂也能抑制肿瘤,但与 HSP90 抑制剂相关的化疗却会导致意想不到的转移。在这里,我们发现 HSP90 抑制剂会导致线粒体损伤,但会刺激低 LC3 诱导的 MDVs 和 MDVs 衍生 EVs 的释放。然而,在 HSP90 抑制作用下,LC3 为什么会减少,MDVs 形成的转录调控机制是什么,这些仍然是未知数。由于TFEB(转录因子EB)是最重要的有丝分裂吞噬转录因子,而HSP90的客户HCFC1(宿主细胞因子C1)调控TFEB的转录,因此在MDVs形成过程中,TFEB、HCFC1和HSP90之间应该存在隐性联系。我们的研究结果支持这样一种观点,即 HSP90 N 端抑制通过减少 HSP90AA1 与 HCFC1 的相互作用来减少 TFEB 的转录,从而阻止 HCFC1 与 TFEB 近端启动子区域结合。TFEB 转录的减少以及 LC3 的减少最终促进了 MDVs 的形成。用微管抑制剂nocodazole(NOC)阻断MDVs的形成可激活HCFC1-TFEB-LC3轴,削弱HSP90抑制剂诱导的MDVs和MDVs衍生EVs的释放,抑制肿瘤细胞球和原发性肝肿瘤的生长,并减少癌细胞向继发性转移部位的外渗。综上所述,这些数据表明,应采用联合疗法来降低 HSP90 抑制剂导致的低 TFEB 触发 MDVs 形成的转移风险。
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引用次数: 0
Atractylenolide I inhibits angiogenesis and reverses sunitinib resistance in clear cell renal cell carcinoma through ATP6V0D2-mediated autophagic degradation of EPAS1/HIF2α. 白术内酯I通过ATP6V0D2介导的EPAS1/HIF2α自噬降解抑制血管生成并逆转透明细胞肾细胞癌的舒尼替尼耐药性。
Pub Date : 2025-03-01 Epub Date: 2024-11-04 DOI: 10.1080/15548627.2024.2421699
Qinyu Li, Kai Zeng, Qian Chen, Chenglin Han, Xi Wang, Beining Li, Jianping Miao, Bolong Zheng, Jihong Liu, Xianglin Yuan, Bo Liu

Clear cell renal cell carcinoma (ccRCC) is tightly associated with VHL (von Hippel-Lindau tumor suppressor) mutation and dysregulated angiogenesis. Accumulating evidence indicates that antiangiogenic treatment abolishing tumor angiogenesis can achieve longer disease-free survival in patients with ccRCC. Atractylenolide I (ATL-I) is one of the main active compounds in Atractylodes macrocephala root extract and exhibits various pharmacological effects, including anti-inflammatory and antitumor effects. In this study, we revealed the potent antitumor activity of ATL-I in ccRCC. ATL-I exhibited robust antiangiogenic capacity by inhibiting EPAS1/HIF2α-mediated VEGFA production in VHL-deficient ccRCC, and it promoted autophagic degradation of EPAS1 by upregulating the ATPase subunit ATP6V0D2 (ATPase H+ transporting V0 subunit d2) to increase lysosomal function and facilitated fusion between autophagosomes and lysosomes. Mechanistically, ATP6V0D2 directly bound to RAB7 and VPS41 and promoted the RAB7-HOPS interaction, facilitating SNARE complex assembly and autophagosome-lysosome fusion. Moreover, ATP6V0D2 promoted autolysosome degradation by increasing the acidification and activity of lysosomes during the later stages of macroautophagy/autophagy. Additionally, we found that ATL-I could decrease the level of EPAS1, which was upregulated in sunitinib-resistant cells, thus reversing sunitinib resistance. Collectively, our findings demonstrate that ATL-I is a robust antiangiogenic and antitumor lead compound with potential clinical application for ccRCC therapy.Abbreviations: ATL-I: atractylenolide I; ATP6V0D2: ATPase H+ transporting V0 subunit d2; CAM: chick chorioallantoic membrane; ccRCC: clear cell renal cell carcinoma; CTSB: cathepsin B; CTSD: cathepsin D; GO: Gene Ontology; HIF-1: HIF1A-ARNT heterodimer; HOPS: homotypic fusion and protein sorting; KDR/VEGFR: kinase insert domain receptor; KEGG: Kyoto Encyclopedia of Genes and Genomes; RCC: renal cell carcinoma; SNARE: soluble N-ethylmaleimide-sensitive factor attachment protein receptor; TCGA: The Cancer Genome Atlas; TEM: transmission electron microscopy; TKI: tyrosine kinase inhibitor; V-ATPase: vacuolar-type H±translocating ATPase; VEGF: vascular endothelial growth factor; VHL: von Hippel-Lindau tumor suppressor.

透明细胞肾细胞癌(ccRCC)与VHL(von Hippel-Lindau肿瘤抑制因子)突变和血管生成失调密切相关。越来越多的证据表明,消除肿瘤血管生成的抗血管生成治疗可以延长ccRCC患者的无病生存期。白术内酯 I(ATL-I)是白术根提取物中的主要活性化合物之一,具有多种药理作用,包括抗炎和抗肿瘤作用。本研究揭示了 ATL-I 在 ccRCC 中的强效抗肿瘤活性。ATL-I通过抑制EPAS1/HIF2α介导的VEGFA生成,在VHL缺陷的ccRCC中表现出强大的抗血管生成能力,并通过上调ATP酶亚基ATP6V0D2(ATP酶H+转运V0亚基d2)促进EPAS1的自噬降解,从而增强溶酶体功能,促进自噬体和溶酶体之间的融合。从机制上讲,ATP6V0D2直接与RAB7和VPS41结合,促进了RAB7-HOPS的相互作用,有利于SNARE复合物的组装和自噬体与溶酶体的融合。此外,在大自噬/自噬的后期阶段,ATP6V0D2通过提高溶酶体的酸化和活性促进自溶酶体降解。此外,我们还发现 ATL-I 能降低舒尼替尼耐药细胞中上调的 EPAS1 水平,从而逆转舒尼替尼耐药。总之,我们的研究结果表明,ATL-I 是一种强效的抗血管生成和抗肿瘤先导化合物,具有临床应用于 ccRCC 治疗的潜力。
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引用次数: 0
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