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Autophagy modulates male fertility in Arabidopsis. 自噬调节拟南芥雄性生殖能力。
Pub Date : 2025-03-01 Epub Date: 2024-12-30 DOI: 10.1080/15548627.2024.2441305
Zhen Lu, He Yan, Hao Wang

Macroautophagy/autophagy is a highly conserved catabolic process in eukaryotes and plays pivotal roles in regulating male fertility and sexual reproduction. In metazoans, mutations in core ATG (autophagy related) proteins frequently result in severe defects in sperm formation and maturation, resulting in male sterility. In contrast, autophagy has traditionally been considered dispensable for reproduction in Arabidopsis thaliana, as most atg mutants can complete fertilization and produce viable progeny without apparent reproductive defects. We recently systematically re-assessed the role of autophagy in Arabidopsis male gametophyte development and fertility using atg5 and atg7 mutants, and the double mutant. These mutants exhibited partial defects in pollen germination, pollen tube growth and seed production compared to the wild type (WT). Furthermore, our findings reveal that autophagy is essential for modulating actin dynamic organization during sperm cell formation within pollen grains and for supporting pollen tube elongation. This is achieved through the selective degradation of actin depolymerizing factors ADF7 and PFN2/Profilin2. NBR1 is identified as a key receptor mediating this process. This study provides valuable insights into the evolutionary conservation and functional divergence of autophagy in modulating male fertility, highlighting distinctions between plant and mammalian systems.

巨噬/自噬是真核生物中高度保守的分解代谢过程,在调节雄性生殖和有性生殖中起着关键作用。在后生动物中,核心ATG(自噬相关)蛋白的突变经常导致精子形成和成熟的严重缺陷,导致男性不育。相比之下,自噬在传统上被认为对拟南芥的繁殖是必不可少的,因为大多数突变体可以完成受精并产生可存活的后代,而没有明显的生殖缺陷。最近,我们利用atg5和atg7突变体以及双突变体系统地重新评估了自噬在拟南芥雄性配子体发育和育性中的作用。与野生型(WT)相比,这些突变体在花粉萌发、花粉管生长和种子产生方面表现出部分缺陷。此外,我们的研究结果表明,自噬在花粉粒内精子细胞形成过程中调节肌动蛋白动态组织和支持花粉管伸长是必不可少的。这是通过选择性降解肌动蛋白解聚因子ADF7和PFN2/Profilin2来实现的。NBR1被认为是介导这一过程的关键受体。这项研究为自噬在调节雄性生殖能力中的进化保护和功能分化提供了有价值的见解,突出了植物和哺乳动物系统之间的区别。
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引用次数: 0
Deciphering melanophagy: role of the PTK2-ITCH-MLANA-OPTN cascade on melanophagy in melanocytes. 解密黑色素吞噬:PTK2-ITCH-MLANA-OPTN 级联在黑色素细胞黑色素吞噬中的作用。
Pub Date : 2025-03-01 Epub Date: 2024-11-12 DOI: 10.1080/15548627.2024.2421695
Na Yeon Park, Doo Sin Jo, Hyun Jun Park, Ji-Eun Bae, Yong Hwan Kim, Joon Bum Kim, Ha Jung Lee, Sung Hyun Kim, Hyunjung Choi, Hyun-Shik Lee, Tamotsu Yoshimori, Dong-Seok Lee, Jin-A Lee, Pansoo Kim, Dong-Hyung Cho

Melanosomes play a pivotal role in skin color and photoprotection. In contrast to the well-elucidated pathway of melanosome biogenesis, the process of melanosome degradation, referred to as melanophagy, is largely unexplored. Previously, we discovered that 3,4,5-trimethoxycinnamate thymol ester (TCTE) effectively inhibits skin pigmentation by activating melanophagy. In this study, we discovered a new regulatory signaling cascade that controls melanophagy in TCTE-treated melanocytes. ITCH (itchy E3 ubiquitin protein ligase) facilitates ubiquitination of the melanosome membrane protein MLANA (melan-A) during TCTE-induced melanophagy. This ubiquitinated MLANA is then recognized by an autophagy receptor protein, OPTN (optineurin). Additionally, a phospho-kinase antibody array revealed that TCTE activates PTK2 (protein tyrosine kinase 2), which phosphorylates ITCH, enhancing the ubiquitination of MLANA. Furthermore, inhibition of either PTK2 or ITCH disrupts the ubiquitination of MLANA and the MLANA-OPTN interaction in TCTE-treated cells. Taken together, our findings highlight the critical role of the PTK2-ITCH-MLANA-OPTN cascade in orchestrating melanophagy progression.Abbreviations: α-MSH: alpha-melanocyte-stimulating hormone; dichlone: 2,3-dichloro-1,4-naphthoquinone; ITCH: itchy E3 ubiquitin protein ligase; MITF: melanocyte inducing transcription factor; MLANA: melan-A; NBR1: NBR1 autophagy cargo receptor; OPTN: optineurin; PINK1: PTEN induced kinase 1; PTK2: protein tyrosine kinase 2; SQSTM1/p62: sequestosome 1; TCTE: 3,4,5-trimethoxycinnamate thymol ester; TPC2: two pore segment channel 2; VDAC1: voltage dependent anion channel 1.

黑色素体在肤色和光保护方面起着关键作用。与已阐明的黑色素小体生物生成途径不同,黑色素小体的降解过程(即黑色素吞噬)在很大程度上尚未被探索。此前,我们发现 3,4,5-三甲氧基肉桂酸胸腺酚酯(TCTE)能通过激活黑色素吞噬作用有效抑制皮肤色素沉着。在这项研究中,我们发现了一种新的调控信号级联,它能控制经 TCTE 处理的黑色素细胞中的黑色素吞噬。在TCTE诱导的黑色素吞噬过程中,ITCH(痒E3泛素蛋白连接酶)促进了黑色素体膜蛋白MLANA(melan-A)的泛素化。泛素化后的 MLANA 会被自噬受体蛋白 OPTN(optineurin)识别。此外,磷酸激酶抗体阵列显示,TCTE 能激活 PTK2(蛋白酪氨酸激酶 2),使 ITCH 磷酸化,从而增强 MLANA 的泛素化。此外,抑制 PTK2 或 ITCH 会破坏 TCTE 处理细胞中 MLANA 的泛素化和 MLANA-OPTN 的相互作用。综上所述,我们的研究结果凸显了 PTK2-ITCH-MLANA-OPTN 级联在协调黑色素吞噬过程中的关键作用。
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引用次数: 0
Janus-like behavior of intrinsically disordered regions in reticulophagy. 网状吞噬中内在无序区域的双面样行为。
Pub Date : 2025-03-01 Epub Date: 2025-01-03 DOI: 10.1080/15548627.2024.2437652
Sergio Alejandro Poveda-Cuevas, Kateryna Lohachova, Borna Markusic, Ivan Dikic, Gerhard Hummer, Ramachandra M Bhaskara

Intrinsically disordered regions (IDRs) are crucial to homeostatic and organellar remodeling pathways. In reticulophagy/ER-phagy, long cytosolic IDR-containing receptors (e.g. RETREG1/FAM134B) house the LC3-interacting region (LIR) motif to recruit the phagophore. The precise functions of the IDR beyond engaging the autophagic machinery are unclear. Here, we comment on the role of the RETREG1-IDR based on our recent computer modeling and molecular dynamics (MD) simulations. Extensive analysis of the RETREG1-IDR indicates a continuum of conformations between expanded and compact structures, displaying a Janus-like feature. Using an adapted MARTINI model, we find that the IDR ensemble properties vary widely depending on the membrane anchor. IDRs alone are sufficient to promote and sense membrane curvature and can act as entropic tethers. When anchored to the Reticulon homology domain (RHD), they adopt compact collapsed conformations, acting as effector scaffolds that amplify RHD membrane remodeling properties, enhancing receptor-clustering and accelerating spontaneous budding. These findings expand the operational scope of IDRs within reticulophagy, offering fresh insights into a mechanistic understanding of membrane remodeling.

内在紊乱区(IDRs)是稳态和细胞器重塑途径的关键。在网状吞噬/ er吞噬中,长胞质含idr受体(如RETREG1/FAM134B)容纳lc3相互作用区(LIR)基序以招募吞噬细胞。除了参与自噬机制外,IDR的确切功能尚不清楚。在这里,我们基于我们最近的计算机建模和分子动力学(MD)模拟来评论RETREG1-IDR的作用。对RETREG1-IDR的广泛分析表明,在扩展结构和紧凑结构之间存在连续的构象,显示出类似两面星的特征。利用一个自适应的MARTINI模型,我们发现IDR系综性质随着膜锚的不同而变化很大。仅idr就足以促进和感知膜曲率,并可作为熵系绳。当锚定在RHD上时,它们采用紧凑的折叠构象,作为效应支架,增强RHD膜重塑特性,增强受体聚集并加速自发出芽。这些发现扩大了idr在网状吞噬中的作用范围,为膜重塑的机制理解提供了新的见解。
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引用次数: 0
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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