ARF6

本研究进一步证实了Arf6通路在炎症性肠病(IBD)中的重要性，并提供了SIRT2作为调控Arf6和治疗IBD的唯一靶点。 炎症性肠病(IBD)，包括溃疡性结肠炎和克罗恩病，是一种慢性消化道炎症性疾病。它每年影响数百万人，可能会使人虚弱，并导致危及生命的并发症。虽然全基因组关联研究已经确定了许多与IBD相关的基因变异，但IBD的确切原因仍不清楚，这使得分子治疗学的发展变得困难。虽然小分子药物和生物制品都可用于治疗IBD，但没有治愈方法，也没有对所有患者有效的治疗方法。因此，仍然需要发现治疗IBD的新方法。 SIRT2是NAD+依赖的蛋白赖氨酸脱酰酶中sirtuin家族的成员。它可以去除蛋白质赖氨酸残基中的乙酰基和长链脂肪酰基。已知SIRT2作用于许多不同的底物蛋白，其抑制已被报道在癌症和神经退行性变中提供有益的效果。 然而，我们对其生物学功能的了解仍然支离破碎，在许多情况下，我们仍然不知道抑制SIRT2是如何产生这样的有益效果的。研究者对IBD的兴趣使我们注意到关于IBD中SIRT2的两个似乎相互矛盾的报告。 这两份报告都涉及SIRT2在葡聚糖硫酸钠(DSS)诱导的小鼠结肠炎模型中的作用。在一份报告中，SIRT2基因敲除小鼠在DSS诱导的结肠炎中的表现比野生型小鼠更差。然而，在另一份报告中，SIRT2特异性小分子抑制剂TM在DSS诱导的结肠炎中对小鼠具有保护作用。这些报道似乎相互矛盾。在这两种情况下，都没有令人信服的分子机制来解释SIRT2在结肠炎中的作用。 图片来源：https://doi.org/10.1073/pnas.2319833121 近日，来自康奈尔大学的研究者们在PNAS杂志上发表了题为“Sirt2 inhibition improves gut epithelial barrier integrity and protects mice from colitis”的文章，该研究揭示了抑制SIRT2改善肠道上皮屏障完整性并保护小鼠免受结肠炎的影响。 SIRT2是一种依赖于烟酰胺腺嘌呤二核苷酸(NAD+)的蛋白质赖氨酸脱酰基酶，可以从许多蛋白质的赖氨酸残基中去除乙酰基和长链脂肪酰基。据报道，它在小鼠模型中影响炎症性肠病(IBD)的症状。然而，有报道称，角色冲突，基因敲除加剧，而药物抑制缓解IBD症状。 这些看似相互矛盾的报告引起了困惑，并阻碍了进一步开发SIRT2抑制剂作为IBD潜在治疗策略的努力。 研究者研究了这些相互矛盾的报告，并阐明了SIRT2在IBD小鼠模型中的作用。我们基本上复制了这些相互矛盾的结果，并证实SIRT2抑制剂的保护作用不是通过脱靶实现的，因为两种非常不同的SIRT2抑制剂(TM和AGK2)在IBD小鼠模型中显示出类似的保护作用。 抑制SIRT2对DSS诱导的结肠炎小鼠的保护作用 图片来源：https://doi.org/10.1073/pnas.2319833121 研究者认为，抑制剂和基因敲除的不同作用是由于SIRT2抑制剂只抑制SIRT2的部分而不是全部活性。观察到SIRT2的PROTAC降解物不能保护IBD模型中的小鼠，这与SIRT2基因敲除相似，证实了这一假设。 该研究提供了一个有趣的例子，其中基因敲除和药物抑制不一致，并强调了开发底物依赖的抑制剂的重要性。重要的是，研究者证明了抑制SIRT2在IBD中的作用是通过抑制Arf6介导的E-钙粘蛋白的内吞作用来调节肠上皮屏障，E-钙粘蛋白是一种对肠上皮完整性至关重要的蛋白质。这一机制的理解进一步支持SIRT2作为治疗IBD的有前途的治疗靶点。 一种通过抑制SIRT2调控DSS诱导的结肠炎的模型 图片来源：https://doi.org/10.1073/pnas.2319833121 本研究证实了关于SIRT2在DSS诱导的小鼠结肠炎模型中的作用的两个似乎相互矛盾的报告。研究者证实SIRT2基因敲除不提供保护，而SIRT2的小分子抑制剂在DSS结肠炎模型中提供明显的保护。此外，研究者排除了小分子抑制剂的保护作用是由于靶外效应，因为不同实验室开发的两种截然不同的抑制剂都显示出相似的保护作用。此外，PROTAC SIRT2降解子也产生了与SIRT2基因敲除相似的表型。 有趣的是，Arf6通路已经被认为与IBD有关。全基因组关联研究已经确定C1orf106突变与IBD风险增加相关。C1orf106是Arf6全球环境基金的抑制物，与IBD相关的突变扰乱了C1orf106，导致Arf6激活和结肠炎风险增加。 本研究进一步证实了Arf6通路在IBD中的重要性，并提供了SIRT2作为调控Arf6和治疗IBD的唯一靶点。由于先前的研究表明SIRT2抑制剂在小鼠中具有良好的耐受性，并且SIRT2基因敲除小鼠只有非常温和的表型，靶向SIRT2可能是一种安全且有前景的治疗IBD的策略。（生物谷 Bioon.com） 参考文献: Dan Hou et al. Sirt2 inhibition improves gut epithelial barrier integrity and protects mice from colitis. Proc Natl Acad Sci U S A. 2024 Apr 30;121(18):e2319833121. doi:10.1073/pnas.2319833121.

Medical researchers have found a peptide which, when administered intravenously, homes in on the new blood vessels that are forming in damaged tissue. The peptide has been used as a delivery vehicle for therapeutics targeted at regenerating tissues. A new study has discovered that the peptide activates the natural healing mechanism in the tissue, accelerating regeneration. The finding opens new opportunities to treat not only skin wounds, but also any injuries resulting from accidents and traumas, such as ruptured muscles and fractured bones. Professor Tero Järvinen has found a peptide which, when administered intravenously, homes in on the new blood vessels that are forming in damaged tissue. The peptide has been used as a delivery vehicle for therapeutics targeted at regenerating tissues. A new study led by professor Järvinen discovered that the peptide activates the natural healing mechanism in the tissue, accelerating regeneration. The finding opens new opportunities to treat not only skin wounds, but also any injuries resulting from accidents and traumas, such as ruptured muscles and fractured bones. One of the key goals of medical science is to speed up the healing of tissue injuries in a way that would not enable the forming of less functional scar tissue in the affected areas. Professor Tero Järvinen at Tampere University in Finland is leading research that is seeking solutions to achieve this goal. In an earlier study, Järvinen discovered a so-called homing peptide, a small piece of protein that specifically seeks tissue damage via the bloodstream. The homing peptide was named the CAR peptide after its amino acid composition. It was screened out of more than a billion peptides using the screening technology of in vivo phage display. The peptide was used to transport a scar reducing drug to the wounds via systemic administration. Recently, the research group showed that the CAR transport peptide is itself a therapeutic drug. CAR activates a natural healing pathway crucial for tissue regeneration and accelerates wound healing without the need to attach to any kind of drug. The study, reported in a recent issue of Nature Communications, confirmed that the CAR peptide activates the tissue regeneration mechanism that is critical for wound healing by entering the wound through the bloodstream. In the wound, the peptide binds to syndecan-4, a cell membrane receptor. This binding activates the intracellular cytohesin-2 factor, which in turn activates the Arf6 GTPase that triggers cell migration, i.e., the migration of regenerating cells across the damaged area in the wound. By this molecular mechanism, the skin wounds in mice receiving the CAR peptide healed significantly faster than without the therapy. The ensuing scars were also smaller than without treatment. As this syndecan-4 dependent cell migration-mechanism is crucial for the healing of multiple injuries, such as skeletal muscle ruptures and bone fractures, the CAR peptide has multiple clinically relevant indications not just for traumatology, but also surgery and sports medicine. "Syndecan-4-dependent tissue regeneration is a key factor in the healing of several other tissue injuries beyond skin wounds, including muscle ruptures and bone fractures. The CAR peptide we found, which activates this natural healing mechanism, opens completely new possibilities for treating traumas and injuries not only in traumatology but also in surgery and sports injuries. Because the drug molecule actively seeks tissue damage through the bloodstream, the treated injury can be in any part of the body and can be targeted by the CAR peptide therapy," Järvinen explains. Professor Tero Järvinen led the study in cooperation with Academician of Science Erkki Ruoslahti. The research was carried out at Tampere University, Sanford Burnham Prebys Medical Discovery Institute (La Jolla, CA, USA) and at the University of California Santa Barbara (UCSB, CA, USA). Researchers from the University of Liverpool (UK) and the Wellcome Trust Centre for Cell-Matrix Research at the University of Manchester (UK) also participated.

Root hairs represent a low-cost strategy to enhance nutrient uptake because they can significantly increase the nutrient-acquiring surface of plant roots. While primary and lateral roots are stimulated to elongate when plants grow under mild nitrogen deficiency, the existence of such a foraging response for root hairs and its underlying regulatory mechanism remain elusive. Now, researchers have revealed a framework composed of specific molecular players meditating auxin synthesis, transport and signaling that triggers root hair elongation for nitrogen acquisition. Root hairs represent a low-cost strategy to enhance nutrient uptake because they can significantly increase the nutrient-acquiring surface of plant roots. While primary and lateral roots are stimulated to elongate when plants grow under mild nitrogen deficiency, the existence of such a foraging response for root hairs and its underlying regulatory mechanism remain elusive. Now, an international research team led by IPK Leibniz Institute revealed a framework composed of specific molecular players meditating auxin synthesis, transport and signaling that triggers root hair elongation for nitrogen acquisition. The results have been published in the journal Current Biology. Plants have evolved diverse adaptive strategies to optimize the exploration of light and soil resources from their environments. One of the most prominent adaptive responses is the developmental plasticity of their root systems, which enables plants to efficiently forage nutrient pools that fluctuate in space and time. As a crucial component determining the active root surface, root hairs represent a powerful morphological trait to improve water and nutrient acquisition. Root hairs are extensions of epidermal cells that effectively enlarge the root surface area and facilitate soil exploration for water and nutrients. Root hair development starts with cell fate specification, which determines whether an epidermal cell becomes a hair-forming cell (trichoblast) or a hairless cell (atrichoblast). "In our study, we first showed that nitrogen deficiency strongly stimulates root hair elongation in the model species Arabidopsis thaliana and that this response is crucial for plant fitness under low nitrogen," explains Prof. Dr. Nicolaus von Wirén, head of the department "Physiology and Cell Biology" at IPK Leibniz Institute. "And we then integrated transcriptomics, molecular genetics and cell biology approaches to establish that low nitrogen-induced root hair elongation builds on a spatially coordinated auxin signaling cascade that enters the root hair developmental program via the epidermal transcriptional module RHD6-LRL3." The signaling cascade consists of three stages. Through upregulation of the enzymes TAA1 and YUCCA8, low nitrogen increases auxin accumulation in the root apex (step 1, synthesis). Auxin is then directed shootward to the root hair differentiation zone via the transporters AUX1 and PIN2 (step 2, transport). Upon arrival, auxin activates the transcription factors ARF6 and ARF8 to promote the transcriptional module RHD6-LRL3, which is confined to the epidermis and steers root hair elongation in response to low nitrogen (step 3, signaling). "Overall, our results suggest that root hair elongation represents an additional systemically-induced foraging response strategy to explore the soil for nitrogen, gaining even more relevance as nitrogen deficiency becomes more severe," says Dr. Zhongtao Jia, first author of the study. "These findings add a new feature to our understanding of root foraging responses in low-nutrient environments and expand the mechanistic framework of hormone-regulated nutrient sensing in plant roots." Since more abundant and longer root hairs represent a low-cost strategy for plants to bring roots in contact with soil nutrients, understanding how root hair development is regulated by nitrogen provides new breeding targets for developing crops with enhanced nitrogen-uptake efficiency.