Biology of the Cell最新文献

英文中文

Alpha-arrestins Aly1/Art6 and Aly2/Art3 regulate trafficking of the glycerophosphoinositol transporter Git1 and impact phospholipid homeostasis α -抑制因子Aly1/Art6和Aly2/Art3调节甘油磷酸肌醇转运体Git1的运输并影响磷脂稳态

IF 2.7 4区生物学 Q2 Biochemistry, Genetics and Molecular Biology

Biology of the Cell

Pub Date : 2021-09-25 DOI: 10.1111/boc.202100007

Benjamin P. Robinson, Sarah Hawbaker, Annette Chiang, Eric M. Jordahl, Sanket Anaokar, Alexiy Nikiforov, Ray W. Bowman II, Philip Ziegler, Ceara K. McAtee, Jana Patton-Vogt, Allyson F. O'Donnell

Background information

Phosphatidylinositol (PI) is an essential phospholipid, critical to membrane bilayers. The complete deacylation of PI by B-type phospholipases produces intracellular and extracellular glycerophosphoinositol (GPI). Extracellular GPI is transported into the cell via Git1, a member of the Major Facilitator Superfamily of transporters at the yeast plasma membrane. Internalized GPI is degraded to produce inositol, phosphate and glycerol, thereby contributing to these pools. GIT1 gene expression is controlled by nutrient balance, with phosphate or inositol starvation increasing GIT1 expression to stimulate GPI uptake. However, less is known about control of Git1 protein levels or localization.

Results

We find that the α-arrestins, an important class of protein trafficking adaptor, regulate Git1 localization and this is dependent upon their interaction with the ubiquitin ligase Rsp5. Specifically, α-arrestin Aly2 stimulates Git1 trafficking to the vacuole under basal conditions, but in response to GPI-treatment, either Aly1 or Aly2 promote Git1 vacuole trafficking. Cell surface retention of Git1, as occurs in aly1∆ aly2∆ cells, is linked to impaired growth in the presence of exogenous GPI and results in increased uptake of radiolabeled GPI, suggesting that accumulation of GPI somehow causes cellular toxicity. Regulation of α-arrestin Aly1 by the protein phosphatase calcineurin improves steady-state and substrate-induced trafficking of Git1, however, calcineurin plays a larger role in Git1 trafficking beyond regulation of α-arrestins. Interestingly, loss of Aly1 and Aly2 increased phosphatidylinositol-3-phosphate on the limiting membrane of the vacuole, and this was further exacerbated by GPI addition, suggesting that the effect is partially linked to Git1. Loss of Aly1 and Aly2 leads to increased incorporation of inositol label from [³H]-inositol-labelled GPI into PI, confirming that internalized GPI influences PI balance and indicating a role for the a-arrestins in this regulation.

Conclusions

The α-arrestins Aly1 and Aly2 are novel regulators of Git1 trafficking with previously unanticipated roles in controlling phospholipid distribution and balance.

Significance

To our knowledge, this is the first example of α-arrestin regulation of phosphatidyliniositol-3-phosphate levels. In future studies it will be exciting to determine if other α-arrestins similarly alter PI and PIPs to change the cellular landscape.

磷脂酰肌醇(PI)是一种必需的磷脂，对膜双层至关重要。b型磷脂酶对PI的完全去酰化产生细胞内和细胞外甘油磷酸肌醇(GPI)。胞外GPI通过Git1转运到细胞中，Git1是酵母质膜转运蛋白主要促进物超家族的一员。内化的GPI被降解为肌醇、磷酸盐和甘油，从而有助于这些池。GIT1基因表达受营养平衡控制，磷酸盐或肌醇饥饿会增加GIT1表达以刺激GPI摄取。然而，对Git1蛋白水平或定位的控制知之甚少。结果我们发现α-阻滞蛋白是一类重要的蛋白质转运适配器，它调节Git1的定位，这依赖于它们与泛素连接酶Rsp5的相互作用。具体来说，α-阻滞蛋白Aly2在基础条件下刺激Git1向液泡转运，但在gpi处理下，Aly1或Aly2均促进Git1液泡转运。在aly1∆aly2∆细胞中，Git1的细胞表面保留与外源性GPI存在下的生长受损有关，并导致放射性标记GPI的摄取增加，这表明GPI的积累在某种程度上导致细胞毒性。蛋白磷酸酶钙调磷酸酶(calcalineurin)对α-阻滞蛋白Aly1的调控改善了稳态和底物诱导的Git1转运，然而，钙调磷酸酶在Git1转运中发挥的作用比α-阻滞蛋白更大。有趣的是，Aly1和Aly2的缺失增加了液泡极限膜上的磷脂酰肌醇-3-磷酸，GPI的加入进一步加剧了这种情况，这表明这种效果部分与Git1有关。Aly1和Aly2的缺失导致肌醇标签从[3H]-肌醇标记的GPI增加到PI中，证实内化的GPI影响PI平衡，并表明a-拦阻蛋白在这一调节中起作用。结论α-抑制因子Aly1和Aly2是Git1转运的新调控因子，在控制磷脂分布和平衡方面具有先前未被发现的作用。据我们所知，这是α-抑制蛋白调控磷脂酰肌醇-3-磷酸水平的第一个例子。在未来的研究中，确定其他α-抑制因子是否类似地改变PI和pip以改变细胞景观将是令人兴奋的。

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引用次数: 3

A new pancreatic adenocarcinoma-derived organoid model of acquired chemoresistance to FOLFIRINOX: First insight of the underlying mechanisms 一种新的胰腺腺癌衍生的对FOLFIRINOX获得性化疗耐药的类器官模型:首次了解其潜在机制

IF 2.7 4区生物学 Q2 Biochemistry, Genetics and Molecular Biology

Biology of the Cell

Pub Date : 2021-09-24 DOI: 10.1111/boc.202100003

Elsa Hadj Bachir, Charles Poiraud, Sonia Paget, Nicolas Stoup, Soumaya El Moghrabi, Belinda Duchêne, Nathalie Jouy, Antonino Bongiovanni, Meryem Tardivel, Louis-Bastien Weiswald, Marie Vandepeutte, César Beugniez, Fabienne Escande, Emmanuelle Leteurtre, OrgaRES consortium, Laurent Poulain, Chann Lagadec, Pascal Pigny, Nicolas Jonckheere, Florence Renaud, Stephanie Truant, Isabelle Van Seuningen, Audrey Vincent

Background Information

Although improvements have been made in the management of pancreatic adenocarcinoma (PDAC) during the past 20 years, the prognosis of this deadly disease remains poor with an overall 5-year survival under 10%. Treatment with FOLFIRINOX, a combined regimen of 5-fluorouracil, irinotecan (SN-38) and oxaliplatin, is nonetheless associated with an excellent initial tumour response and its use has allowed numerous patients to go through surgery while their tumour was initially considered unresectable. These discrepancies between initial tumour response and very low long-term survival are the consequences of rapidly acquired chemoresistance and represent a major therapeutic frontier. To our knowledge, a model of resistance to the combined three drugs has never been described due to the difficulty of modelling the FOLFIRINOX protocol both in vitro and in vivo. Patient-derived tumour organoids (PDO) are the missing link that has long been lacking in the wide range of epithelial cancer models between 2D adherent cultures and in vivo xenografts. In this work we sought to set up a model of PDO with resistance to FOLFIRINOX regimen that we could compare to the paired naive PDO.

Results

We first extrapolated physiological concentrations of the three drugs using previous pharmacodynamics studies and bi-compartmental elimination models of oxaliplatin and SN-38. We then treated PaTa-1818x naive PDAC organoids with six cycles of 72 h-FOLFIRINOX treatment followed by 96 h interruption. Thereafter, we systematically compared treated organoids to PaTa-1818x naive organoids in terms of growth, proliferation, viability and expression of genes involved in cancer stemness and aggressiveness.

Conclusions

We reproductively obtained resistant organoids FoxR that significantly showed less sensitivity to FOLFORINOX treatment than the PaTa-1818x naive organoids from which they were derived. Our resistant model is representative of the sequential steps of chemoresistance observed in patients in terms of growth arrest (proliferation blockade), residual disease (cell quiescence/dormancy) and relapse.

Significance

To our knowledge, this is the first genuine in vitro model of resistance to the three drugs in combined therapy. This new PDO model will be a great asset for the discovery of acquired chemoresistance mechanisms, knowledge that is mandatory before offering new therapeutic strategies for pancreatic cancer.

虽然在过去的20年里，胰腺腺癌(PDAC)的治疗已经取得了进展，但这种致命疾病的预后仍然很差，总5年生存率低于10%。FOLFIRINOX是一种5-氟尿嘧啶、伊立替康(n -38)和奥沙利铂的联合治疗方案，尽管如此，它的治疗与良好的初始肿瘤反应有关，并且它的使用允许许多患者在最初被认为无法切除的肿瘤时进行手术。这些最初的肿瘤反应和非常低的长期生存之间的差异是快速获得的化疗耐药的后果，代表了一个主要的治疗前沿。据我们所知，由于FOLFIRINOX方案在体外和体内建模的困难，从未描述过对三种药物联合耐药的模型。患者源性肿瘤类器官(PDO)是2D贴壁培养和体内异种移植之间广泛的上皮癌模型中长期缺乏的缺失环节。在这项工作中，我们试图建立一个对FOLFIRINOX方案耐药的PDO模型，我们可以将其与配对的幼稚PDO进行比较。我们首先利用先前的药理学研究和奥沙利铂和SN-38的双室消除模型推断出三种药物的生理浓度。然后，我们对PaTa-1818x初始PDAC类器官进行了6个周期的72 h- folfirinox治疗，随后中断96 h。随后，我们系统地比较了经过处理的类器官与未经PaTa-1818x处理的类器官在生长、增殖、活力以及与癌症干性和侵袭性相关的基因表达方面的差异。结论:我们获得了耐药类器官FoxR，其对FOLFORINOX治疗的敏感性明显低于其衍生的PaTa-1818x原始类器官。我们的耐药模型代表了在生长停止(增殖阻断)、残留疾病(细胞静止/休眠)和复发方面观察到的患者化疗耐药的顺序步骤。据我们所知，这是第一个真正的三种药物联合治疗的体外耐药模型。这种新的PDO模型将成为发现获得性化疗耐药机制的重要资产，这是在提供胰腺癌新治疗策略之前必须了解的知识。

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引用次数: 8

Decreased proliferation of aged rat beta cells corresponds with enhanced expression of the cell cycle inhibitor p27KIP1 衰老大鼠β细胞增殖减少与细胞周期抑制剂p27KIP1的表达增强相对应

IF 2.7 4区生物学 Q2 Biochemistry, Genetics and Molecular Biology

Biology of the Cell

Pub Date : 2021-09-14 DOI: 10.1111/boc.202100035

Talon J. Aitken, Jacqueline E. Crabtree, Daelin M. Jensen, Kavan H. Hess, Brennan R. Leininger, Jeffery S. Tessem

Background

Over 400 million people are diabetic. Type 1 and type 2 diabetes are characterized by decreased functional β-cell mass and, consequently, decreased glucose-stimulated insulin secretion. A potential intervention is transplantation of β-cell containing islets from cadaveric donors. A major impediment to greater application of this treatment is the scarcity of transplant-ready β-cells. Therefore, inducing β-cell proliferation ex vivo could be used to expand functional β-cell mass prior to transplantation. Various molecular pathways are sufficient to induce proliferation of young β-cells; however, aged β-cells are refractory to these proliferative signals. Given that the majority of cadaveric donors fit an aged demographic, defining the mechanisms that impede aged β-cell proliferation is imperative.

Results

We demonstrate that aged rat (5-month-old) β-cells are refractory to mitogenic stimuli that otherwise induce young rat (5-week-old) β-cell proliferation. We hypothesized that this change in proliferative capacity could be due to differences in cyclin-dependent kinase inhibitor expression. We measured levels of p16^INK4a, p15^INK4b, p18^INK4c, p19^INK4d, p21^CIP1, p27^KIP1 and p57^KIP2 by immunofluorescence analysis. Our data demonstrates an age-dependent increase of p27^KIP1 in rat β-cells by immunofluorescence and was validated by increased p27^KIP1 protein levels by western blot analysis. Interestingly, HDAC1, which modulates the p27^KIP1 promoter acetylation state, is downregulated in aged rat islets. These data demonstrate increased p27^KIP1 protein levels at 5 months of age, which may be due to decreased HDAC1 mediated repression of p27^KIP1 expression.

Significance

As the majority of transplant-ready β-cells come from aged donors, it is imperative that we understand why aged β-cells are refractory to mitogenic stimuli. Our findings demonstrate that increased p27^KIP1 expression occurs early in β-cell aging, which corresponds with impaired β-cell proliferation. Furthermore, the correlation between HDAC1 and p27 levels suggests that pathways that activate HDAC1 in aged β-cells could be leveraged to decrease p27^KIP1 levels and enhance β-cell proliferation.

超过4亿人患有糖尿病。1型和2型糖尿病的特点是功能性β细胞质量减少，因此葡萄糖刺激的胰岛素分泌减少。一种潜在的干预方法是移植尸体供体中含有胰岛的β细胞。这种疗法的一个主要障碍是缺乏可移植的β细胞。因此，在体外诱导β细胞增殖可以在移植前扩大功能β细胞群。多种分子途径足以诱导年轻β细胞增殖;然而，衰老的β细胞对这些增殖信号是不耐受的。鉴于大多数尸体捐献者都属于老年人群，确定阻碍老年β细胞增殖的机制势在必行。结果我们证明老龄大鼠(5个月大)β细胞对有丝分裂刺激是不耐受的，否则会诱导幼鼠(5周大)β细胞增殖。我们假设这种增殖能力的变化可能是由于细胞周期蛋白依赖性激酶抑制剂表达的差异。我们用免疫荧光法测定了p16INK4a、p15INK4b、p18INK4c、p19INK4d、p21CIP1、p27KIP1和p57KIP2的水平。我们的数据通过免疫荧光显示大鼠β细胞中p27KIP1的年龄依赖性增加，并通过western blot分析证实了p27KIP1蛋白水平的增加。有趣的是，调节p27KIP1启动子乙酰化状态的HDAC1在老年大鼠胰岛中下调。这些数据表明，5月龄时p27KIP1蛋白水平升高，这可能是由于HDAC1介导的p27KIP1表达抑制减少所致。由于大多数可供移植的β-细胞来自老年供体，我们必须了解为什么老年β-细胞对有丝分裂刺激难以耐受。我们的研究结果表明，p27KIP1表达的增加发生在β细胞衰老的早期，这与β细胞增殖受损相对应。此外，HDAC1和p27水平之间的相关性表明，衰老β细胞中激活HDAC1的途径可以降低p27KIP1水平并增强β细胞的增殖。

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引用次数: 3

Role of regulatory C-terminal motifs in synaptic confinement of LRRTM2 调节性c端基序在LRRTM2突触约束中的作用

IF 2.7 4区生物学 Q2 Biochemistry, Genetics and Molecular Biology

Biology of the Cell

Pub Date : 2021-09-09 DOI: 10.1111/boc.202100026

Konstantina Liouta, Julia Chabbert, Sebastien Benquet, Béatrice Tessier, Vincent Studer, Matthieu Sainlos, Joris De Wit, Olivier Thoumine, Ingrid Chamma

Leucine Rich Repeat Transmembrane proteins (LRRTMs) are neuronal cell adhesion molecules involved in synapse development and plasticity. LRRTM2 is the most synaptogenic isoform of the family, and its expression is strongly restricted to excitatory synapses in mature neurons. However, the mechanisms by which LRRTM2 is trafficked and stabilized at synapses remain unknown. Here, we examine the role of LRRTM2 intracellular domain on its membrane expression and stabilization at excitatory synapses, using a knock-down strategy combined to single molecule tracking and super-resolution dSTORM microscopy. We show that LRRTM2 operates an important shift in mobility after synaptogenesis in hippocampal neurons. Knock-down of LRRTM2 during synapse formation reduced excitatory synapse density in mature neurons. Deletion of LRRTM2 C-terminal domain abolished the compartmentalization of LRRTM2 in dendrites and disrupted its synaptic enrichment. Furtheremore, we show that LRRTM2 diffusion is increased in the absence of its intracellular domain, and that the protein is more dispersed at synapses. Surprisingly, LRRTM2 confinement at synapses was strongly dependent on a YxxC motif in the C-terminal domain, but was independent of the PDZ-like binding motif ECEV. Finally, the nanoscale organization of LRRTM2 at excitatory synapses depended on its C-terminal domain, with involvement of both the PDZ-binding and YxxC motifs. Altogether, these results demonstrate that LRRTM2 trafficking and enrichment at excitatory synapses are dependent on its intracellular domain.

富亮氨酸重复跨膜蛋白(LRRTMs)是参与突触发育和可塑性的神经细胞粘附分子。LRRTM2是该家族中突触原性最强的亚型，其表达强烈局限于成熟神经元的兴奋性突触。然而，LRRTM2在突触中运输和稳定的机制尚不清楚。在这里，我们使用敲除策略结合单分子跟踪和超分辨率dSTORM显微镜研究了LRRTM2胞内结构域在兴奋性突触的膜表达和稳定中的作用。我们发现LRRTM2在海马神经元突触发生后的活动中起着重要的作用。成熟神经元突触形成过程中LRRTM2的敲除降低了兴奋性突触密度。LRRTM2 c端结构域的缺失消除了LRRTM2在树突中的区隔化，破坏了其突触富集。此外，我们发现LRRTM2在缺乏胞内结构域时扩散增加，并且该蛋白在突触中更分散。令人惊讶的是，突触上的LRRTM2约束强烈依赖于c端结构域的YxxC基序，但不依赖于pdz样结合基序ECEV。最后，LRRTM2在兴奋性突触中的纳米级组织依赖于其c端结构域，pdz结合基序和YxxC基序都参与其中。总之，这些结果表明LRRTM2在兴奋性突触的转运和富集依赖于其胞内结构域。

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引用次数: 1

Quantitative dSTORM super-resolution microscopy localizes Aurora kinase A/AURKA in the mitochondrial matrix 定量dSTORM超分辨率显微镜定位线粒体基质中的极光激酶A/AURKA

IF 2.7 4区生物学 Q2 Biochemistry, Genetics and Molecular Biology

Biology of the Cell

Pub Date : 2021-08-31 DOI: 10.1111/boc.202100021

Béatrice Durel, Charles Kervrann, Giulia Bertolin

Background information

Mitochondria are dynamic organelles playing essential metabolic and signaling functions in cells. Their ultrastructure has largely been investigated with electron microscopy (EM) techniques. However, quantifying protein-protein proximities using EM is extremely challenging. Super-resolution microscopy techniques as direct stochastic optical reconstruction microscopy (dSTORM) now provide a fluorescent-based, quantitative alternative to EM. Recently, super-resolution microscopy approaches including dSTORM led to valuable advances in our knowledge of mitochondrial ultrastructure, and in linking it with new insights in organelle functions. Nevertheless, dSTORM is mostly used to image integral mitochondrial proteins, and there is little or no information on proteins transiently present at this compartment. The cancer-related Aurora kinase A/AURKA is a protein localized at various subcellular locations, including mitochondria.

Results

We first demonstrate that dSTORM coupled to GcoPS can resolve protein proximities within individual submitochondrial compartments. Then, we show that dSTORM provides sufficient spatial resolution to visualize and quantify the most abundant pool of endogenous AURKA in the mitochondrial matrix, as previously shown for overexpressed AURKA. In addition, we uncover a smaller pool of AURKA localized at the OMM, which could have a potential functional readout. We conclude by demonstrating that aldehyde-based fixatives are more specific for the OMM pool of the kinase instead.

Conclusions

Our results indicate that dSTORM coupled to GcoPS colocalization analysis is a suitable approach to explore the compartmentalization of non-integral mitochondrial proteins as AURKA, in a qualitative and quantitative manner. This method also opens up the possibility of analyzing the proximity between AURKA and its multiple mitochondrial partners with exquisite spatial resolution, thereby allowing novel insights into the mitochondrial functions controlled by AURKA.

Significance

Probing and quantifying the presence of endogenous AURKA – a cell cycle-related protein localized at mitochondria – in the different organelle subcompartments, using quantitative dSTORM super-resolution microscopy.

线粒体是细胞中具有重要代谢和信号功能的动态细胞器。用电子显微镜(EM)技术研究了它们的超微结构。然而，使用EM定量蛋白质-蛋白质接近度是极具挑战性的。超分辨率显微镜技术，如直接随机光学重建显微镜(dSTORM)，现在为EM提供了一种基于荧光的定量替代方法。最近，包括dSTORM在内的超分辨率显微镜方法在我们对线粒体超微结构的了解方面取得了有价值的进展，并将其与细胞器功能的新见解联系起来。然而，dSTORM主要用于成像完整的线粒体蛋白质，并且很少或没有关于瞬时存在于该隔室的蛋白质的信息。与癌症相关的极光激酶A/AURKA是一种定位于各种亚细胞位置的蛋白质，包括线粒体。我们首先证明了dSTORM与GcoPS结合可以解决单个亚线粒体区室内的蛋白质接近性。然后，我们证明dSTORM提供了足够的空间分辨率来可视化和量化线粒体基质中最丰富的内源性AURKA库，如先前对过表达的AURKA所示。此外，我们在OMM发现了一个较小的AURKA池，它可能具有潜在的功能读数。我们通过证明醛基固定剂对激酶的OMM池更具特异性而得出结论。我们的研究结果表明，dSTORM结合GcoPS共定位分析是一种合适的方法，可以定性和定量地探索非完整线粒体蛋白作为AURKA的区区化。这种方法也为分析AURKA及其多个线粒体伴侣之间的接近性提供了可能性，具有精细的空间分辨率，从而对AURKA控制的线粒体功能有了新的认识。意义:利用dSTORM超分辨率显微镜检测和量化不同细胞器亚室中内源性AURKA(一种定位于线粒体的细胞周期相关蛋白)的存在。

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引用次数: 1

Apoptosis induction by the stem cell factor LIN28A 干细胞因子LIN28A诱导细胞凋亡

IF 2.7 4区生物学 Q2 Biochemistry, Genetics and Molecular Biology

Biology of the Cell

Pub Date : 2021-08-26 DOI: 10.1111/boc.202100011

Yael Attali-Padael, Leah Armon, Achia Urbach

Background information

Lin28A and its paralog Lin28B are RNA binding proteins expressed in stem and progenitor cells, regulating the balance between their proliferation and differentiation. In-vivo and in-vitro experiments have shown that overexpression of these genes leads to abnormal cell proliferation, which results in many cases in cell transformation and tumor formation.

Results

Here we show, for the first time, that Lin28A overexpression can also lead to the opposite effect, i.e. apoptosis induction. We further demonstrate that this effect is specific to Lin28A but not to Lin28B and that it is mediated via the Let-7 independent pathway in a complex mechanism that involves at least several proteins.

Conclusions and Significance

This unexpected observation suggests that cell fate regulation by Lin28 is dependent on a specific cellular/genetic context. Unraveling the cellular and molecular mechanisms underlying this Lin28A overexpression effect may pave the way for novel tumor therapeutic strategies, as Lin28 is commonly expressed in many types of tumors but not in most normal adult cells.

背景资料Lin28A及其平行体Lin28B是在干细胞和祖细胞中表达的RNA结合蛋白，调节干细胞和祖细胞增殖和分化的平衡。体内和体外实验表明，这些基因的过表达会导致细胞增殖异常，在许多情况下导致细胞转化和肿瘤形成。我们首次发现，Lin28A过表达也会导致相反的效果，即诱导细胞凋亡。我们进一步证明，这种作用是Lin28A特异性的，而不是Lin28B，并且它是通过一个复杂的机制介导的，该机制不依赖于Let-7途径，涉及至少几种蛋白质。这一意想不到的观察结果表明，Lin28对细胞命运的调控依赖于特定的细胞/遗传环境。揭示这种Lin28A过表达效应的细胞和分子机制可能为新的肿瘤治疗策略铺平道路，因为Lin28通常在许多类型的肿瘤中表达，而不是在大多数正常成人细胞中表达。

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引用次数: 1

Issue Information 问题信息

IF 2.7 4区生物学 Q2 Biochemistry, Genetics and Molecular Biology

Biology of the Cell

Pub Date : 2021-06-01 DOI: 10.1111/boc.202170012

引用次数: 0

The NANOTUMOR consortium - Towards the Tumor Cell Atlas. 纳米肿瘤联盟-迈向肿瘤细胞图谱。

IF 2.7 4区生物学 Q2 Biochemistry, Genetics and Molecular Biology

Biology of the Cell

Pub Date : 2021-06-01 Epub Date: 2021-02-26 DOI: 10.1111/boc.202000135

Florent Colin, Kristine Schauer, Ali Hamiche, Pierre Martineau, Jean-Paul Borg, Jan Bednar, Giulia Bertolin, Luc Camoin, Yves Collette, Stephan Dimitrov, Isabelle Fournier, Vincent Hyenne, Marco A Mendoza-Parra, Xavier Morelli, Philippe Rondé, Izabela Sumara, Marc Tramier, Patrick Schultz, Jacky G Goetz

Cancer is a multi-step disease where an initial tumour progresses through critical steps shaping, in most cases, life-threatening secondary foci called metastases. The oncogenic cascade involves genetic, epigenetic, signalling pathways, intracellular trafficking and/or metabolic alterations within cancer cells. In addition, pre-malignant and malignant cells orchestrate complex and dynamic interactions with non-malignant cells and acellular matricial components or secreted factors within the tumour microenvironment that is instrumental in the progression of the disease. As our aptitude to effectively treat cancer mostly depends on our ability to decipher, properly diagnose and impede cancer progression and metastasis formation, full characterisation of molecular complexes and cellular processes at play along the metastasis cascade is crucial. For many years, the scientific community lacked adapted imaging and molecular technologies to accurately dissect, at the highest resolution possible, tumour and stromal cells behaviour within their natural microenvironment. In that context, the NANOTUMOR consortium is a French national multi-disciplinary workforce which aims at a providing a multi-scale characterisation of the oncogenic cascade, from the atomic level to the dynamic organisation of the cell in response to genetic mutations, environmental changes or epigenetic modifications. Ultimately, this program aims at identifying new therapeutic targets using innovative drug design.

癌症是一个多阶段的疾病，在大多数情况下，最初的肿瘤经过几个关键步骤发展，形成威胁生命的次要病灶，称为转移灶。致癌级联包括遗传、表观遗传、信号通路、细胞内运输和/或癌细胞内的代谢改变。此外，恶性前和恶性细胞与肿瘤微环境中的非恶性细胞和非细胞物质成分或分泌因子之间存在复杂和动态的相互作用，这有助于疾病的进展。由于我们有效治疗癌症的能力在很大程度上取决于我们破译、正确诊断和阻止癌症进展和转移形成的能力，因此充分表征分子复合物和细胞过程在转移级联中发挥作用至关重要。多年来，科学界缺乏适应的成像和分子技术，以尽可能高的分辨率准确解剖肿瘤和基质细胞在其自然微环境中的行为。在这种背景下，NANOTUMOR联盟是一个法国国家多学科的工作队伍，旨在提供致癌级联的多尺度特征，从原子水平到细胞的动态组织，以响应基因突变、环境变化或表观遗传修饰。最终，该计划旨在利用创新药物设计确定新的治疗靶点。

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引用次数: 1

Intracellular host cell membrane remodelling induced by SARS-CoV-2 infection in vitro. SARS-CoV-2感染诱导的体外细胞内宿主细胞膜重塑。

IF 2.7 4区生物学 Q2 Biochemistry, Genetics and Molecular Biology

Biology of the Cell

Pub Date : 2021-06-01 Epub Date: 2021-03-03 DOI: 10.1111/boc.202000146

Lucio Ayres Caldas, Fabiana Avila Carneiro, Fabio Luis Monteiro, Ingrid Augusto, Luiza Mendonça Higa, Kildare Miranda, Amilcar Tanuri, Wanderley de Souza

Background information: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection induces an alteration in the endomembrane system of the mammalian cells. In this study, we used transmission electron microscopy and electron tomography to investigate the main structural alterations in the cytoplasm of Vero cells infected with a SARS-CoV-2 isolate from São Paulo state (Brazil).

Results: Different membranous structures derived from the zippered endoplasmic reticulum were observed along with virus assembly through membrane budding. Also, we demonstrated the occurrence of annulate lamellae in the cytoplasm of infected cells and the presence of virus particles in the perinuclear space.

Conclusions and significance: This study contributes to a better understanding of the cell biology of SARS-CoV-2 and the mechanisms of the interaction of the virus with the host cell that promote morphological changes, recruitment of organelles and cell components, in a context of a virus-induced membrane remodelling.

背景资料:严重急性呼吸综合征冠状病毒-2 (SARS-CoV-2)感染诱导哺乳动物细胞内膜系统发生改变。在这项研究中，我们使用透射电子显微镜和电子断层扫描研究了来自巴西圣保罗州的SARS-CoV-2分离物感染Vero细胞细胞质的主要结构变化。结果:随着病毒通过膜出芽组装，在拉链内质网中观察到不同的膜结构。此外，我们还证实了在感染细胞的细胞质中出现环状片层，并且在核周空间中存在病毒颗粒。结论与意义:本研究有助于更好地理解SARS-CoV-2的细胞生物学，以及在病毒诱导的膜重构背景下，病毒与宿主细胞相互作用促进形态变化、细胞器和细胞成分募集的机制。

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引用次数: 15

Editorial. 社论。

IF 2.7 4区生物学 Q2 Biochemistry, Genetics and Molecular Biology

Biology of the Cell

Pub Date : 2021-06-01 DOI: 10.1111/boc.202100028

Julien Husson

Mechanobiology is an emerging field at the crossroads between biology, physics, mechanics, bioengineering and materials science. It investigates how mechanics can influence cell function: how cells sense and respond to external mechanical properties and forces, and how they generate forces and adapt their mechanical properties to perform functions as varied as adhesion, migration, differentiation or immune response, to name a few. A growing interest for this field is establishing a corpus of evidence suggesting that potentially any cell, of any type, can sense mechanical inputs from its environment and adapt to them. A new horizon opens up for a more comprehensive description of biological processes that includes their mechanical component. Furthermore, because external mechanical cues are involved in many pathological contexts, understanding the interplay between mechanical inputs and cell response should bring new insights into many pathologies, including cancer, atherosclerosis or evasion from immune response. This themed issue on mechanobiology covers a variety of topics at the cellular and subcellular scale. Three contributions focus on immune cells. Since pioneering studies on the biophysics of leukocytes done decades ago, a growing corpus of knowledge has been accumulated on some myeloid cells such as neutrophils. However, surprising discoveries about these foot soldiers of innate immunity are yet to come, including the way they move to explore their environment. In this issue, Garcia-Seyda et al. (2021) lead the way by showing that neutrophils can swim to reach and phagocyte their target. Mechanics of myeloid cells other than neutrophils remain to be fully explored, and Bashant et al. (2020) review how mechanical properties of myeloid cells can be quantified using recently developed high-throughput deformability cytometry. The authors review how these mechanical properties can be influenced by several factors including: differentiation, priming by cytokines and other soluble molecules or mechanical stimulation, disease and pharmacological treatment. On another front of immunobiophysics, T cells attract a lot of attention given their central role in adaptive immunity and recent revolutions in cancer immunotherapy. T cells use a complex recognition machinery to identify presented antigens. This recognition is known to be mechanosensitive, but understanding the details of this process remains the focus of active work. Before forming a synapse, T cells need to arrest on an antigen-presenting cell (APC), which is yet another process where mechanics play a role. Chabaud et al. (2020) review how mechanical forces generated at the T cell–APC interface and beard by specific bonds between T cell receptors and antigens, and adhesive bonds, regulate the arrest of T cells. This themed issue goes also subcellular with the contribution of Allard et al. (2021), which describes how the shape of membrane tubules can be remodelled by the actin cytoskeleton.

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引用次数: 0

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