更新于：2024-09-19

AHI1

更新于：2024-09-19

基本信息

别名

Abelson helper integration site 1、Abelson helper integration site 1 protein homolog、AHI-1

+ [5]

简介

Involved in vesicle trafficking and required for ciliogenesis, formation of primary non-motile cilium, and recruitment of RAB8A to the basal body of primary cilium. Component of the tectonic-like complex, a complex localized at the transition zone of primary cilia and acting as a barrier that prevents diffusion of transmembrane proteins between the cilia and plasma membranes. Involved in neuronal differentiation. As a positive modulator of classical Wnt signaling, may play a crucial role in ciliary signaling during cerebellum embryonic development (PubMed:21623382).

关联

100 项与 AHI1 相关的临床结果

登录后查看更多信息

100 项与 AHI1 相关的转化医学

登录后查看更多信息

0 项与 AHI1 相关的专利（医药）

登录后查看更多信息

202

项与 AHI1 相关的文献（医药）

2024-12-01·Cellular and Molecular Life Sciences

GR/Ahi1 regulates WDR68-DYRK1A binding and mediates cognitive impairment in prenatally stressed offspring

Article

作者: Zeng, Hongtao ; Zhao, Zejun ; Song, Yueyang ; Wang, Bin ; Zhao, Yan ; Yu, Xi ; Shi, Haixia ; Shi, Yajun ; Wei, Bin ; Sun, Miao

Accumulating research shows that prenatal exposure to maternal stress increases the risk of behavioral and mental health problems for offspring later in life. However, how prenatal stress affects offspring behavior remains unknown. Here, we found that prenatal stress (PNS) leads to reduced Ahi1, decreased synaptic plasticity and cognitive impairment in offspring. Mechanistically, Ahi1 and GR stabilize each other, inhibit GR nuclear translocation, promote Ahi1 and WDR68 binding, and inhibit DYRK1A and WDR68 binding. When Ahi1 deletion or prenatal stress leads to hyperactivity of the HPA axis, it promotes the release of GC, leading to GR nuclear translocation and Ahi1 degradation, which further inhibits the binding of Ahi1 and WDR68, and promotes the binding of DYRK1A and WDR68, leading to elevated DYRK1A, reduced synaptic plasticity, and cognitive impairment. Interestingly, we identified RU486, an antagonist of GR, which increased Ahi1/GR levels and improved cognitive impairment and synaptic plasticity in PNS offspring. Our study contributes to understanding the signaling mechanisms of prenatal stress-mediated cognitive impairment in offspring.

2024-08-01·JNCI: Journal of the National Cancer Institute

Editor’s Note to: Targeting Primitive Chronic Myeloid Leukemia Cells by Effective Inhibition of a New AHI-1–BCR-ABL–JAK2 Complex

2024-05-01·Cell and Tissue Research

Joubert syndrome-derived induced pluripotent stem cells show altered neuronal differentiation in vitro

Article

作者: Pollara, Lidia ; Diprima, Santo ; Leuzzi, Vincenzo ; Monti, Maria Cristina ; Morelli, Marco J ; Gener, Blanca ; Fischetto, Rita ; Giordano, Lucio ; Sottile, Virginie ; Giliani, Silvia Clara ; Ali, Eltahir ; Tardivo, Silvia ; De Mori, Roberta ; Valente, Enza Maria

AbstractJoubert syndrome (JS) is a recessively inherited congenital ataxia characterized by hypotonia, psychomotor delay, abnormal ocular movements, intellectual disability, and a peculiar cerebellar and brainstem malformation, the “molar tooth sign.” Over 40 causative genes have been reported, all encoding for proteins implicated in the structure or functioning of the primary cilium, a subcellular organelle widely present in embryonic and adult tissues. In this paper, we developed an in vitro neuronal differentiation model using patient-derived induced pluripotent stem cells (iPSCs), to evaluate possible neurodevelopmental defects in JS. To this end, iPSCs from four JS patients harboring mutations in distinct JS genes (AHI1, CPLANE1, TMEM67, and CC2D2A) were differentiated alongside healthy control cells to obtain mid-hindbrain precursors and cerebellar granule cells. Differentiation was monitored over 31 days through the detection of lineage-specific marker expression by qRT-PCR, immunofluorescence, and transcriptomics analysis. All JS patient-derived iPSCs, regardless of the mutant gene, showed a similar impairment to differentiate into mid-hindbrain and cerebellar granule cells when compared to healthy controls. In addition, analysis of primary cilium count and morphology showed notable ciliary defects in all differentiating JS patient-derived iPSCs compared to controls. These results confirm that patient-derived iPSCs are an accessible and relevant in vitro model to analyze cellular phenotypes connected to the presence of JS gene mutations in a neuronal context.

项与 AHI1 相关的新闻（医药）

2022-09-09

·生物谷

《细胞研究》：苏州大学团队破解抑郁症损害免疫系统之谜！

随着近年来人民生活质量的提升，人们在追求丰富物质生活的同时也越来越关注精神的健康。抑郁症作为一种常见的精神性疾病也走入了大家的视野。随着近年来人民生活质量的提升，人们在追求丰富物质生活的同时也越来越关注精神的健康。抑郁症作为一种常见的精神性疾病也走入了大家的视野。抑郁症是一种常见于成年人，并且能显著降低患者生活质量的一种精神性疾病。长期处于抑郁状态的人们生活焦虑，精神萎靡，并且伴随着机体免疫力下降。据统计，大约有15%的重度抑郁患者最终因不能忍受这种状态而选择自杀[1-2]。抑郁症患者经常会伴随着很多身体疾病，但是目前很少有对这两者之间的关系进行研究报道[3]。近日，来自苏州大学生命科学医学研究院郑慧教授课题组和神经科学研究所徐兴顺教授课题组合作回答了为什么抑郁患者更容易被病毒感染。相关研究已发表在Cell Research杂志。这项研究揭示了抑郁诱导的抗病毒免疫功能障碍的详细机制，加深了人们对抑郁症患者更容易被病毒感染的高敏感性的理解。论文首页[4] 之前有研究表明抑郁症与下丘脑和垂体中Abelson helper整合位点1（AHI1）表达相关[5]。且AHI1主要表达在巨噬细胞、上皮细胞以及成纤维细胞上。研究人员发现，重度抑郁症患者（MDD）比健康人的外周血单个核细胞（PBMC）中AHI1的mRNA表达更低，这种现象在巨噬细胞上更加明显。该结果也在使用限制空间的抑郁小鼠模型中得到了验证。那巨噬细胞上AHI1表达降低对免疫功能有什么影响呢？在Ahi1缺陷的小鼠模型中，研究人员观察到干扰素诱导家族因子（ISGs）显著下调表达。因此，研究人员推测Ahi1缺陷的细胞抗病毒能力会受到影响。随后研究人员通过病毒感染Ahi1敲除的小鼠模型实验验证了以上猜测。缺失Ahi1表达的巨噬细胞在被病毒感染时会丧失对病毒的抵抗能力。前面的测序结果已经表明，AhI1缺失会造成ISGs信号下调。研究人员进一步探索了AhI1与ISGs之间更加详细的分子机制。有文献表明Tyk2、JAK1等都是传递IFN-I信号活化的初始调控单元[6]。于是研究人员检测了AhI1沉默后的巨噬细胞中IFN-I信号通路相关分子JAK1、STAT1、STAT2以及Tyk2的变化，发现只有Tyk2的蛋白表达显著降低。这表明AHI1可以调节细胞中Tyk2蛋白的表达水平。研究人员使用脉冲追踪测定法来分析AHI1对Tyk2蛋白稳定性的影响，结果显示巨噬细胞中缺失AHI1会加速Tyk2蛋白的降解。进一步，研究人员在抑郁小鼠模型中也观察到Tyk2表达降低。并且在MDD患者的外周血单核细胞中也发现相同的现象。这些发现表明，抑郁小鼠和人类的AHI1表达降低会影响Tyk2蛋白稳定性以及随后的IFN-I信号传导活性。 AHI1调节Tyk2蛋白稳定性，研究人员猜想AHI1可能会影响Tyk2的泛素化修饰。实验结果显示，广谱去泛素化酶抑制剂PR-619完全抵消了AHI1介导的Tyk2蛋白水平上调。通过对潜在的与AHI1相互作用蛋白的质谱分析，研究人员注意到了去泛素酶OTUD1。OTUD1敲除显著抑制了AHI1介导的Tyk2蛋白水平表达的上调，进一步分析显示，OTUD1以AHI1依赖性方式调节K48连接的Tyk2泛素化。下丘脑-垂体-肾上腺系统（HPA）对于抑郁的调节具有关键作用。已有研究表明精氨酸加压素（AVP）在抑郁症患者中表达上调[8]。有趣的是，研究人员发现，在原代巨噬细胞中精氨酸加压素诱导的Tyk2蛋白表达降低是依赖于AHI1的。于是，研究人员猜想高水平的精氨酸加压素可以降低AHI1以及Tyk2的表达，从而抑制IFN-I信号及抗病毒免疫活性。为了验证以上猜想，研究人员使用剂量为50ng/kg的精氨酸加压素进行小鼠给药实验。结果显示，给药后的小鼠外周血单核细胞中的AHI1的表达水平及脾脏中的Tyk2蛋白表达水平与对照组相比显著降低。同时给药后的小鼠外周血单核细胞中的ISGs信号（lfit1, Rsad2, Mx1）也均显著降低。也就是说，抑郁通过精氨酸加压素下调AHI1的表达从而降低机体的抗病毒免疫应答能力。因此如何能够提高AHI1的表达水平就显得至关重要。通过对一些临床药物的筛选，研究人员注意到止痛药美普他酚（Meptazinol）可以显著促进原代巨噬细胞中的Ahi1 mRNA表达。使用美普他酚处理两种巨噬细胞系，均能显著促进AHI1和Tyk2剂量依赖性表达增加。而AHI1敲除之后又会下调Tyk2的表达水平。通过对抑郁小鼠模型的持续两天的（10mg/kg）的给药，研究人员发现相比未处理的小鼠，实验组小鼠的多脏器中AHI1和Tyk2的蛋白水平均显著升高。而当实验组小组受到病毒感染时，美普他酚显著上调了模型鼠中脾脏和肺脏的ISGs表达水平，抑制了病毒感染。总的来说，研究人员发现了抑郁症患者免疫下降的机制，并证实了美普他酚可以改善IFN-I信号传导并补救抑郁小鼠模型的抗病毒免疫。由于抑郁症患者处于病毒感染的高风险，感染病毒后又会进一步加剧疾病进展。因此，研究人员的发现可以为减轻抑郁患者的症状和改善其生活质量提供帮助。参考文献： [1] ALVAREZ RETUERTO A I, CANTOR R M, GLEESON J G, et al. Association of common variants in the Joubert syndrome gene (AHI1) with autism [J]. Hum Mol Genet, 2008, 17(24): 3887-96. [2] GUZE S B, ROBINS E. Suicide and primary affective disorders [J]. Br J Psychiatry, 1970, 117(539): 437-8. [3] MOUSSAVI S, CHATTERJI S, VERDES E, et al. Depression, chronic diseases, and decrements in health: results from the World Health Surveys [J]. Lancet, 2007, 370(9590): 851-8. [4] ZHANG H G, WANG B, YANG Y, et al. Depression compromises antiviral innate immunity via the AVP-AHI1-Tyk2 axis [J]. Cell Res, 2022. [5] XU X, YANG H, LIN Y F, et al. Neuronal Abelson helper integration site-1 (Ahi1) deficiency in mice alters TrkB signaling with a depressive phenotype [J]. Proc Natl Acad Sci U S A, 2010, 107(44): 19126-31. [6] LUO Q, WU X, ZHAO P, et al. OTUD1 Activates Caspase-Independent and Caspase-Dependent Apoptosis by Promoting AIF Nuclear Translocation and MCL1 Degradation [J]. Adv Sci (Weinh), 2021, 8(8): 2002874. [7] ZHANG L, LIU J, QIAN L, et al. Induction of OTUD1 by RNA viruses potently inhibits innate immune responses by promoting degradation of the MAVS/TRAF3/TRAF6 signalosome [J]. PLoS Pathog, 2018, 14(5): e1007067. [8] VAN LONDEN L, GOEKOOP J G, VAN KEMPEN G M, et al. Plasma levels of arginine vasopressin elevated in patients with major depression [J]. Neuropsychopharmacology, 1997, 17(4): 284-92.