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Dynamic mitophagy trajectories hallmark brain aging. 动态线粒体自噬轨迹是大脑衰老的标志。
Pub Date : 2025-02-01 Epub Date: 2024-12-19 DOI: 10.1080/15548627.2024.2426115
Anna Rappe, Thomas G McWilliams

Studies using mitophagy reporter mice have established steady-state landscapes of mitochondrial destruction in mammalian tissues, sparking intense interest in basal mitophagy. Yet how basal mitophagy is modified by healthy aging in diverse brain cell types has remained a mystery. We present a comprehensive spatiotemporal analysis of mitophagy and macroautophagy dynamics in the aging mammalian brain, reporting critical region- and cell-specific turnover trajectories in a longitudinal study. We demonstrate that the physiological regulation of mitophagy in the mammalian brain is cell-specific, dynamic and complex. Mitophagy increases significantly in the cerebellum and hippocampus during midlife, while remaining unchanged in the prefrontal cortex (PFC). Conversely, macroautophagy decreases in the hippocampus and PFC, but remains stable in the cerebellum. We also describe emergent lysosomal heterogeneity, with subsets of differential acidified lysosomes accumulating in the aging brain. We further establish midlife as a critical inflection point for autophagy regulation, which may be important for region-specific vulnerability and resilience to aging. By mapping in vivo autophagy dynamics at the single cell level within projection neurons, interneurons and microglia, to astrocytes and secretory cells, we provide a new framework for understanding brain aging and offer potential targets and timepoints for further study and intervention in neurodegenerative diseases.

使用线粒体自噬报告小鼠的研究已经在哺乳动物组织中建立了线粒体破坏的稳态景观,引发了对基础线粒体自噬的强烈兴趣。然而,不同脑细胞类型的健康衰老如何改变基础有丝分裂仍然是一个谜。我们对衰老哺乳动物大脑中的线粒体自噬和巨噬动力学进行了全面的时空分析,并在一项纵向研究中报告了关键区域和细胞特异性的转换轨迹。我们证明了哺乳动物大脑中线粒体自噬的生理调节是细胞特异性的、动态的和复杂的。在中年时期,小脑和海马的线粒体自噬显著增加,而前额叶皮层(PFC)的线粒体自噬保持不变。相反,巨噬在海马和PFC中减少,但在小脑中保持稳定。我们还描述了出现的溶酶体异质性,不同酸化溶酶体亚群在衰老的大脑中积累。我们进一步确定中年是自噬调节的关键拐点,这可能对特定区域的衰老脆弱性和恢复力很重要。通过在投射神经元、中间神经元和小胶质细胞、星形胶质细胞和分泌细胞的单细胞水平上绘制体内自噬动力学,我们为理解脑衰老提供了一个新的框架,并为进一步研究和干预神经退行性疾病提供了潜在的靶点和时间点。
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引用次数: 0
ABHD8 antagonizes inflammation by facilitating chaperone-mediated autophagy-mediated degradation of NLRP3. ABHD8 通过促进伴侣介导的 NLRP3 自噬降解来拮抗炎症。
Pub Date : 2025-02-01 Epub Date: 2024-09-03 DOI: 10.1080/15548627.2024.2395158
Shuai Yang, Mengqiu Li, Guangyu Lian, Yaoxing Wu, Jun Cui, Liqiu Wang

The NLRP3 inflammasome is a multiprotein complex that plays a vital role in the innate immune system in response to microbial infections and endogenous danger signals. Aberrant activation of the NLRP3 inflammasome is implicated in a spectrum of inflammatory and autoimmune diseases, emphasizing the necessity for precise regulation of the NLRP3 inflammasome to maintain immune homeostasis. The protein level of NLRP3 is a limiting step for inflammasome activation, which must be tightly controlled to avoid detrimental consequences. Here, we demonstrate that ABHD8, a member of the α/β-hydrolase domain-containing (ABHD) family, interacts with NLRP3 and promotes its degradation through the chaperone-mediated autophagy (CMA) pathway. ABHD8 acts as a scaffold to recruit palmitoyltransferase ZDHHC12 to NLRP3 for its palmitoylation as well as subsequent CMA-mediated degradation. Notably, ABHD8 deficiency results in the stabilization of NLRP3 protein and promotes NLRP3 inflammasome activation. We further confirm that ABHD8 overexpression ameliorates LPS- or alum-triggered NLRP3 inflammasome activation in vivo. Interestingly, the nucleocapsid (N) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) impairs the ABHD8-NLRP3 association, resulting in an elevation in NLRP3 protein level and excessive inflammasome activation. These findings demonstrate that ABHD8 May represent a potential therapeutic target in conditions associated with NLRP3 inflammasome dysregulation.Abbreviations: 3-MA: 3-methyladenine; ABHD: α/β-hydrolase domain-containing; BMDMs: Bone marrow-derived macrophages; CFZ: carfilzomib; CHX: cycloheximide; CMA: chaperone-mediated autophagy; CQ: chloroquine; DAMPs: danger/damage-associated molecular patterns; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; LAMP2A: lysosomal associated membrane protein 2A; NH4Cl: ammonium chloride; NLRP3: NLR family pyrin domain containing 3; PAMPs: pathogen-associated molecular patterns; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2.

NLRP3 炎性体是一种多蛋白复合物,在先天性免疫系统中对微生物感染和内源性危险信号起着至关重要的作用。NLRP3 炎症小体的异常激活与一系列炎症和自身免疫性疾病有关,这强调了精确调节 NLRP3 炎症小体以维持免疫平衡的必要性。NLRP3 蛋白水平是炎性体激活的一个限制步骤,必须加以严格控制以避免有害后果。在这里,我们证明了α/β-含水解酶结构域(ABHD)家族成员ABHD8与NLRP3相互作用,并通过伴侣介导的自噬(CMA)途径促进其降解。ABHD8 是一种支架,可将棕榈酰基转移酶 ZDHHC12 招募到 NLRP3 上,使其发生棕榈酰化,并随后通过 CMA 介导降解。值得注意的是,ABHD8 缺乏会导致 NLRP3 蛋白的稳定,并促进 NLRP3 炎性体的激活。我们进一步证实,ABHD8的过表达可改善体内LPS或明矾诱导的NLRP3炎性体活化。有趣的是,严重急性呼吸系统综合征冠状病毒2(SARS-CoV-2)的核壳(N)蛋白会损害ABHD8与NLRP3的关联,导致NLRP3蛋白水平升高和炎性体过度激活。这些研究结果表明,在与 NLRP3 炎症小体失调相关的疾病中,ABHD8 可能是一个潜在的治疗靶点:缩写:3-MA:3-甲基腺嘌呤;ABHD:含α/β-水解酶结构域;BMDMs:CFZ:卡非佐米;CHX:环己亚胺;CMA:伴侣介导的自噬;CQ:氯喹;DAMPs:危险/损伤相关分子模式;HSPA8/HSC70:热休克蛋白家族 A(Hsp70)成员 8;LAMP2A:溶酶体相关膜蛋白 2:NH4Cl:氯化铵;NLRP3:NLR 家族含吡咯啉结构域 3;PAMPs:病原体相关分子模式;SARS-CoV-2:严重急性呼吸系统综合征冠状病毒 2。
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引用次数: 0
UBAC2 serves as a reticulophagy receptor to suppress inflammatory responses. UBAC2 是抑制炎症反应的网状吞噬受体。
Pub Date : 2025-02-01 Epub Date: 2024-11-27 DOI: 10.1080/15548627.2024.2431341
Xing He, Shouheng Jin

Reticulophagy selectively degrades fragments of the endoplasmic reticulum (ER) through macroautophagy/autophagy to maintain ER homeostasis. The deficiency of reticulophagy results in the unfolded protein response (UPR), which is a crucial clue to the pathogenesis of inflammatory diseases. However, the detailed mechanism underlying the cross-regulation between reticulophagy and inflammatory diseases remains largely unclear. Recently, we have revealed that UBAC2 (UBA domain containing 2) is essential for controlling ER homeostasis as a novel reticulophagy receptor. MARK2 catalyzes the phosphorylation of UBAC2 at serine (S) 223, hence facilitating the progression of reticulophagy and inhibiting ER stress-induced inflammatory responses.

网吞噬通过大自噬/自噬选择性地降解内质网(ER)碎片,以维持ER的平衡。网吞噬功能的缺乏会导致未折叠蛋白反应(UPR),这是炎症性疾病发病机制的重要线索。然而,网吞噬与炎症性疾病之间交叉调节的详细机制仍不清楚。最近,我们发现 UBAC2(含 UBA 结构域的 2)作为一种新型网吞噬受体对控制 ER 稳态至关重要。MARK2 可催化 UBAC2 在丝氨酸(S)223 处的磷酸化,从而促进网吞噬的进展并抑制 ER 应激诱导的炎症反应。
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引用次数: 0
Epg5 links proteotoxic stress due to defective autophagic clearance and epileptogenesis in Drosophila and Vici syndrome patients. Epg5将果蝇和维西综合征患者自噬清除缺陷导致的蛋白毒性压力与癫痫发生联系起来。
Pub Date : 2025-02-01 Epub Date: 2024-10-10 DOI: 10.1080/15548627.2024.2405956
Celine Deneubourg, Hormos Salimi Dafsari, Simon Lowe, Aitana Martinez-Cotrina, David Mazaud, Seo Hyun Park, Virginia Vergani, Amanda Almacellas Barbanoj, Reza Maroofian, Luisa Averdunk, Ehsan Ghayoor-Karimiani, Sandeep Jayawant, Cyril Mignot, Boris Keren, Renate Peters, Arveen Kamath, Lauren Mattas, Sumit Verma, Arpana Silwal, Felix Distelmaier, Henry Houlden, Gabriele Lignani, Adam Antebi, James Jepson, Heinz Jungbluth, Manolis Fanto

Epilepsy is a common neurological condition that arises from dysfunctional neuronal circuit control due to either acquired or innate disorders. Autophagy is an essential neuronal housekeeping mechanism, which causes severe proteotoxic stress when impaired. Autophagy impairment has been associated to epileptogenesis through a variety of molecular mechanisms. Vici Syndrome (VS) is the paradigmatic congenital autophagy disorder in humans due to recessive variants in the ectopic P-granules autophagy tethering factor 5 (EPG5) gene that is crucial for autophagosome-lysosome fusion and autophagic clearance. Here, we used Drosophila melanogaster to study the importance of Epg5 in development, aging, and seizures. Our data indicate that proteotoxic stress due to impaired autophagic clearance and seizure-like behaviors correlate and are commonly regulated, suggesting that seizures occur as a direct consequence of proteotoxic stress and age-dependent neurodegenerative progression. We provide complementary evidence from EPG5-mutated patients demonstrating an epilepsy phenotype consistent with Drosophila predictions.Abbreviations: AD: Alzheimer's disease; ALS-FTD: Amyotrophic Lateral Sclerosis-FrontoTemoporal Dementia; DART: Drosophila Arousal Tracking; ECoG: electrocorticogram; EEG: electroencephalogram; EPG5: ectopic P-granules 5 autophagy tethering factor; KA: kainic acid; MBs: mushroom bodies; MRI magnetic resonance imaging; MTOR: mechanistic target of rapamycin kinase; PD: Parkinson's disease; TSC: TSC complex; VS: Vici syndrome.

癫痫是一种常见的神经系统疾病,由后天或先天性疾病导致的神经元回路控制功能障碍引起。自噬是一种重要的神经元管家机制,一旦受损,就会导致严重的蛋白毒性压力。自噬功能受损通过多种分子机制与癫痫发生有关。维奇综合征(VS)是人类先天性自噬疾病的典型代表,其病因是异位P颗粒自噬系链因子5(EPG5)基因的隐性变异,该基因对自噬体-溶酶体融合和自噬清除至关重要。在这里,我们利用黑腹果蝇研究了 EPG5 在发育、衰老和癫痫发作中的重要性。我们的数据表明,自噬清除能力受损导致的蛋白毒性应激与癫痫发作样行为相关且共同受到调控,这表明癫痫发作是蛋白毒性应激和年龄依赖性神经退行性进展的直接后果。我们提供了来自 EPG5 基因突变患者的补充证据,这些患者的癫痫表型与果蝇的预测一致。
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引用次数: 0
ER quality control through reticulophagy and protein secretion. 通过网状吞噬和蛋白质分泌控制 ER 质量。
Pub Date : 2025-02-01 Epub Date: 2024-11-27 DOI: 10.1080/15548627.2024.2431340
Cathena Meiling Li, Yong-Keun Jung

The endoplasmic reticulum (ER) is the site of multiple cellular events and maintaining its quality control is thus crucial for cell homeostasis. Through a morphology-based gain-of-function screen, we identified the cytosolic protein FKBPL as a regulator of reticulophagy. With multiple protein-binding domains, FKBPL binds to the ER-resident CKAP4, acting as a bridge that connects the ER to the phagophore and facilitating the delivery of ER contents for lysosomal degradation. The FKBPL-CKAP4 axis is essential for both basal and stress-induced reticulophagy. Loss of the FKBPL-CKAP4 interaction attenuates reticulophagy and enhances protein secretion via microvesicle shedding. Here, we propose a dual role for the FKBPL-CKAP4 axis in regulating reticulophagy and protein secretion.

内质网(ER)是多种细胞事件的发生场所,因此保持其质量控制对细胞的平衡至关重要。通过基于形态学的功能增益筛选,我们发现细胞膜蛋白 FKBPL 是网状吞噬的调控因子。FKBPL具有多个蛋白结合域,能与驻留在ER上的CKAP4结合,成为连接ER和吞噬细胞的桥梁,促进ER内容物被输送到溶酶体降解。FKBPL-CKAP4 轴对于基础和应激诱导的网状吞噬都是必不可少的。失去 FKBPL-CKAP4 的相互作用会减弱网吞噬作用,并通过微囊脱落增强蛋白质分泌。在此,我们提出了 FKBPL-CKAP4 轴在调节网状吞噬和蛋白质分泌中的双重作用。
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引用次数: 0
Drosophila aux orchestrates the phosphorylation-dependent assembly of the lysosomal V-ATPase in glia and contributes to SNCA/α-synuclein degradation.
Pub Date : 2025-01-29 DOI: 10.1080/15548627.2024.2442858
Shiping Zhang, Linfang Wang, Shuanglong Yi, Yu-Ting Tsai, Yi-Hsuan Cheng, Yu-Tung Lin, Chia-Ching Lin, Yi-Hua Lee, Honglei Wang, Shuhua Li, Ruiqi Wang, Yang Liu, Wei Yan, Chang Liu, Kai-Wen He, Margaret S Ho

Glia contribute to the neuropathology of Parkinson disease (PD), but how they react opposingly to be beneficial or detrimental under pathological conditions, like promoting or eliminating SNCA/α-syn (synuclein alpha) inclusions, remains elusive. Here we present evidence that aux (auxilin), the Drosophila homolog of the PD risk factor GAK (cyclin G associated kinase), regulates the lysosomal degradation of SNCA/α-syn in glia. Lack of glial GAK/aux increases the lysosome number and size, regulates lysosomal acidification and hydrolase activity, and ultimately blocks the degradation of substrates including SNCA/α-syn. Whereas SNCA/α-syn accumulates prominently in lysosomes devoid of glial aux, levels of injected SNCA/α-syn preformed fibrils are further enhanced in the absence of microglial GAK. Mechanistically, aux mediates phosphorylation at the serine 543 of Vha44, the V1 C subunit of the vacuolar-type H+-translocating ATPase (V-ATPase), and regulates its assembly to control proper acidification of the lysosomal milieu. Expression of Vha44, but not the Vha44 variant lacking S543 phosphorylation, restores lysosome acidity, locomotor deficits, and DA neurodegeneration upon glial aux depletion, linking this pathway to PD. Our findings identify a phosphorylation-dependent switch controlling V-ATPase assembly for lysosomal SNCA/α-syn degradation in glia. Targeting the clearance of glial SNCA/α-syn inclusions via this lysosomal pathway could potentially be a therapeutic approach to ameliorate the disease progression in PD.Abbreviation: aux: auxilin; GAK: cyclin G associated kinase; LTG: LysoTracker Green; LTR: LysoTracker Red; MR: Magic Red; PD: Parkinson disease; SNCA/a-syn: synuclein alpha; V-ATPase: vacuolar-type H+-translocating ATPase.

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引用次数: 0
Induction of lysosome biogenesis is a novel function of the CGAS-STING1 pathway. 诱导溶酶体生物发生是CGAS-STING1通路的一个新功能。
Pub Date : 2025-01-27 DOI: 10.1080/15548627.2025.2456064
Yinfeng Xu, Wei Wan

Induction of macroautophagy/autophagy has been established as an important function elicited by the CGAS-STING1 pathway during pathogen infection. However, it remains unknown whether lysosomal activity within the cell in these settings is concurrently enhanced to cope with the increased autophagic flux. Recently, we discovered that the CGAS-STING1 pathway elevates the degradative capacity of the cell by activating lysosome biogenesis. Intriguingly, we found that STING1-induced GABARAP lipidation, rather than TBK1 activation, serves as the key mediator triggering the nuclear translocation of transcription factor TFEB and enhances the expression of lysosome-related genes. Mechanistically, we demonstrated that lipidated GABARAP on single membranes, regulated by the V-ATPase-ATG16L1 axis, sequesters the FLCN-FNIP complex to abolish its function toward RRAGC and RRAGD, leading to a specific impairment of MTORC1-dependent phosphorylation of TFEB and resulting in its subsequent nuclear translocation. Functionally, we showed that STING1-induced lysosome biogenesis is essential for the clearance of cytoplasmic DNA and the elimination of invading pathogens. Collectively, our findings underscore the induction of lysosome biogenesis as a novel function of the CGAS-STING1 pathway.Abbreviation: ATG: autophagy-related; cGAMP: cyclic GMP-AMP; CGAS: cyclic GMP-AMP synthase; GABARAP: GABA type A receptor-associated protein; MEF: mouse embryonic fibroblast; MTOR: mechanistic target of rapamycin kinase; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1; TFEB: transcription factor EB.

诱导巨噬/自噬已被确定为CGAS-STING1通路在病原体感染过程中引发的重要功能。然而,在这些情况下,细胞内的溶酶体活性是否同时增强以应对增加的自噬通量仍不清楚。最近,我们发现CGAS-STING1通路通过激活溶酶体生物发生来提高细胞的降解能力。有趣的是,我们发现sting1诱导的GABARAP脂化,而不是TBK1激活,是触发转录因子TFEB核易位并增强溶酶体相关基因表达的关键介质。在机制上,我们证明了单膜上脂化的GABARAP,受V-ATPase-ATG16L1轴的调节,隔离FLCN-FNIP复合物以消除其对RRAGC-RRAGD的功能,导致mtorc1依赖性TFEB磷酸化的特异性损伤,并导致其随后的核易位。在功能上,我们发现sting - 1诱导的溶酶体生物发生对于清除细胞质DNA和消除入侵病原体至关重要。总的来说,我们的研究结果强调了作为CGAS-STING1途径的一种新功能诱导溶酶体生物发生。徐银;电子邮件:yinfengxu@hnfnu.edu.cn;湖南第一师范大学,湖南省长沙市丰林三路1015号,410205
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引用次数: 0
Survival strategies of cancer cells: the role of macropinocytosis in nutrient acquisition, metabolic reprogramming, and therapeutic targeting. 癌细胞的生存策略:巨噬细胞在营养获取、代谢重编程和治疗靶向中的作用。
Pub Date : 2025-01-26 DOI: 10.1080/15548627.2025.2452149
Guoshuai Xu, Qinghong Zhang, Renjia Cheng, Jun Qu, Wenqiang Li
<p><p>Macropinocytosis is a nonselective form of endocytosis that allows cancer cells to largely take up the extracellular fluid and its contents, including nutrients, growth factors, etc. We first elaborate meticulously on the process of macropinocytosis. Only by thoroughly understanding this entire process can we devise targeted strategies against it. We then focus on the central role of the MTOR (mechanistic target of rapamycin kinase) complex 1 (MTORC1) in regulating macropinocytosis, highlighting its significance as a key signaling hub where various pathways converge to control nutrient uptake and metabolic processes. The article covers a comprehensive analysis of the literature on the molecular mechanisms governing macropinocytosis, including the initiation, maturation, and recycling of macropinosomes, with an emphasis on how these processes are hijacked by cancer cells to sustain their growth. Key discussions include the potential therapeutic strategies targeting macropinocytosis, such as enhancing drug delivery via this pathway, inhibiting macropinocytosis to starve cancer cells, blocking the degradation and recycling of macropinosomes, and inducing methuosis - a form of cell death triggered by excessive macropinocytosis. Targeting macropinocytosis represents a novel and innovative approach that could significantly advance the treatment of cancers that rely on this pathway for survival. Through continuous research and innovation, we look forward to developing more effective and safer anti-cancer therapies that will bring new hope to patients.<b>Abbreviation</b>: AMPK: AMP-activated protein kinase; ASOs: antisense oligonucleotides; CAD: carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase; DC: dendritic cell; EGF: epidermal growth factor; EGFR: epidermal growth factor receptor; ERBB2: erb-b2 receptor tyrosine kinase 2; ESCRT: endosomal sorting complex required for transport; GAP: GTPase-activating protein; GEF: guanine nucleotide exchange factor; GRB2: growth factor receptor bound protein 2; LPP: lipopolyplex; MTOR: mechanistic target of rapamycin kinase; MTORC1: mechanistic target of rapamycin kinase complex 1; MTORC2: mechanistic target of rapamycin kinase complex 2; NSCLC: non-small cell lung cancer; PADC: pancreatic ductal adenocarcinoma; PDPK1: 3-phosphoinositide dependent protein kinase 1; PI3K: phosphoinositide 3-kinase; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; PtdIns(3,4,5)P<sub>3</sub>: phosphatidylinositol-(3,4,5)-trisphosphate; PtdIns(4,5)P<sub>2</sub>: phosphatidylinositol-(4,5)-bisphosphate; PTT: photothermal therapies; RAC1: Rac family small GTPase 1; RPS6: ribosomal protein S6; RPS6KB1: ribosomal protein S6 kinase B1; RTKs: receptor tyrosine kinases; SREBF: sterol regulatory element binding transcription factor; TFEB: transcription factor EB; TNBC: triple-negative breast cancer; TSC2: TSC complex subunit 2; ULK1: unc-51 like autophagy activating kinase 1; UPS: ubiquitin-prot
巨饮作用是一种非选择性的内吞作用,它允许癌细胞大量摄取细胞外液及其内容物,包括营养物质、生长因子等。我们首先详细阐述了巨红细胞增多症的过程。只有彻底了解这整个过程,我们才能制定有针对性的策略。然后,我们将重点放在MTOR(雷帕霉素激酶机制靶点)复合物1 (MTORC1)在调节巨噬细胞作用中的核心作用上,强调其作为关键信号枢纽的重要性,各种途径汇聚在一起控制营养摄取和代谢过程。本文全面分析了巨噬细胞增多症的分子机制,包括巨噬细胞小体的起始、成熟和再循环,并强调了这些过程是如何被癌细胞劫持以维持其生长的。关键讨论包括针对巨噬细胞增多症的潜在治疗策略,如通过该途径增强药物输送,抑制巨噬细胞增多症使癌细胞饥饿,阻断巨噬细胞体的降解和再循环,以及诱导methuosis(一种由过度巨噬细胞增多症引发的细胞死亡形式)。靶向巨红细胞增多症代表了一种新颖的创新方法,可以显著推进依赖于这种途径生存的癌症的治疗。通过不断的研究和创新,我们期待开发出更有效、更安全的抗癌疗法,为患者带来新的希望。
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引用次数: 0
Mammalian nucleophagy: process and function. 哺乳动物的核噬:过程和功能。
Pub Date : 2025-01-26 DOI: 10.1080/15548627.2025.2455158
Fujian Ji, Enyong Dai, Rui Kang, Daniel J Klionsky, Tong Liu, Yu Hu, Daolin Tang, Kun Zhu

The nucleus is a highly specialized organelle that houses the cell's genetic material and regulates key cellular activities, including growth, metabolism, protein synthesis, and cell division. Its structure and function are tightly regulated by multiple mechanisms to ensure cellular integrity and genomic stability. Increasing evidence suggests that nucleophagy, a selective form of autophagy that targets nuclear components, plays a critical role in preserving nuclear integrity by clearing dysfunctional nuclear materials such as nuclear proteins (lamins, SIRT1, and histones), DNA-protein crosslinks, micronuclei, and chromatin fragments. Impaired nucleophagy has been implicated in aging and various pathological conditions, including cancer, neurodegeneration, autoimmune disorders, and neurological injury. In this review, we focus on nucleophagy in mammalian cells, discussing its mechanisms, regulation, and cargo selection, as well as evaluating its therapeutic potential in promoting human health and mitigating disease.Abbreviations: 5-FU: 5-fluorouracil; AMPK, AMP-activated protein kinase; ATG, autophagy related; CMA, chaperone-mediated autophagy; DRPLA: dentatorubral-pallidoluysian atrophy; ER, endoplasmic reticulum; ESCRT: endosomal sorting complex required for transport; HOPS, homotypic fusion and vacuole protein sorting; LIR: LC3-interacting region; MEFs: mouse embryonic fibroblasts; mRNA: messenger RNA; MTORC1: mechanistic target of rapamycin kinase complex 1; PCa: prostate cancer; PE: phosphatidylethanolamine; PI3K, phosphoinositide 3-kinase; PtdIns3K: class III phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; rRNA: ribosomal RNA; SCI: spinal cord injury; SCLC: small cell lung cancer; SNARE: soluble N-ethylmaleimide-sensitive factor attachment protein receptor; SupraT: supraphysiological levels of testosterone; TOP1cc: TOP1 cleavage complexes.

细胞核是一种高度特化的细胞器,容纳细胞的遗传物质并调节关键的细胞活动,包括生长、代谢、蛋白质合成和细胞分裂。它的结构和功能受到多种机制的严格调控,以确保细胞的完整性和基因组的稳定性。越来越多的证据表明,核自噬是一种选择性的自噬形式,以核成分为目标,通过清除功能异常的核物质,如核蛋白(层蛋白、SIRT1和组蛋白)、dna -蛋白交联、微核和染色质片段,在保持核完整性方面起着关键作用。核自噬受损与衰老和各种病理状况有关,包括癌症、神经变性、自身免疫性疾病和神经损伤。在这篇综述中,我们将重点讨论哺乳动物细胞中的核自噬,讨论其机制、调节和货物选择,并评估其在促进人类健康和减轻疾病方面的治疗潜力。
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引用次数: 0
The Epstein-Barr virus deubiquitinase BPLF1 regulates stress-induced ribosome UFMylation and reticulophagy.
Pub Date : 2025-01-22 DOI: 10.1080/15548627.2024.2440846
Jiangnan Liu, Noemi Nagy, Carlos Ayala-Torres, Solenne Bleuse, Francisco Aguilar-Alonso, Ola Larsson, Maria G Masucci

The synthesis of membrane and secreted proteins is safeguarded by an endoplasmic reticulum-associated ribosome quality control (ER-RQC) that promotes the disposal of defective translation products by the proteasome or via a lysosome-dependent pathway involving the degradation of portions of the ER by macroautophagy (reticulophagy). The UFMylation of RPL26 on ER-stalled ribosomes is essential for activating the ER-RQC and reticulophagy. Here, we report that the viral deubiquitinase (vDUB) encoded in the N-terminal domain of the Epstein-Barr virus (EBV) large tegument protein BPLF1 hinders the UFMylation of RPL26 on ribosomes that stall at the ER, promotes the stabilization of ER-RQC substrates, and inhibits reticulophagy. The vDUB did not act as a de-UFMylase or interfere with the UFMylation of the ER membrane protein CYB5R3 by the UFL1 ligase. Instead, it copurified with ribosomes in sucrose gradients and abrogated a ZNF598- and LTN1-independent ubiquitination event required for RPL26 UFMylation. Physiological levels of BPLF1 impaired the UFMylation of RPL26 in productively EBV-infected cells, pointing to an important role of the enzyme in regulating the translation quality control that allows the efficient synthesis of viral proteins and the production of infectious virus.Abbreviation: BPLF1, BamH1 P fragment left open readingframe-1; CDK5RAP3, CDK5regulatory subunit associated protein 3; ChFP, mCherry fluorescent protein; DDRGK1, DDRGKdomain containing 1; EBV, Epstein-Barr virus; eGFP, enhancedGFP; ER-RQC, endoplasmicreticulum-associated ribosome quality control; LCL, EBV-carryinglymphoblastoid cell line; GFP, green fluorescent protein; RQC, ribosome quality control; SRP, signal recognition particle; UFM1, ubiquitin fold modifier 1; UFL1, UFM1 specific ligase 1.

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Autophagy
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