AbstractImportin β-superfamily nuclear import receptors (NIRs) mitigate mislocalization and aggregation of RNA-binding proteins (RBPs), like FUS and TDP-43, which are implicated in neurodegenerative diseases. NIRs potently disaggregate RBPs by recognizing their nuclear localization signal (NLS). However, disease-causing mutations in NLS compromise NIR binding and activity.

摘要importinβ-超家族核输入受体（NIRs）减轻了与神经退行性疾病有关的RNA结合蛋白（RBPs）的错误定位和聚集，如FUS和TDP-43。NIRs通过识别其核定位信号（NLS）来有效地分解RBP。但是，NLS中的致病突变会损害NIR的结合和活性。

Here, we define features that characterize the anti-aggregation activity of NIR and NLS. We find that high binding affinity between NIR and NLS, and optimal NLS location relative to the aggregating domain plays a role in determining NIR disaggregation activity. A designed FUS chimera (FUSIBB), carrying the importin β binding (IBB) domain, is solubilized by importin β in vitro, translocated to the nucleus in cultured cells, and downregulates the expression of endogenous FUS.

在这里，我们定义了表征NIR和NLS抗聚集活性的特征。我们发现NIR和NLS之间的高结合亲和力，以及相对于聚集结构域的最佳NLS位置在确定NIR解聚活性中起作用。设计的带有输入蛋白β结合（IBB）结构域的FUS嵌合体（FUSBB）在体外被输入蛋白β溶解，转移到培养细胞的细胞核中，并下调内源性FUS的表达。

In this study, we posit that guiding the mutual recognition of NLSs and NIRs will aid the development of therapeutics, illustrated by the highly soluble FUSIBB replacing the aggregation-prone endogenous FUS..

在这项研究中，我们认为指导NLS和NIRs的相互识别将有助于治疗的发展，如高度可溶性的FUSIBB取代易聚集的内源性FUS所示。。

IntroductionCytoplasmic mislocalization and aggregation of nuclear RNA-binding proteins (RBPs) with Prion-like domain (PrLD) is a shared pathological hallmark of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and multisystem proteinopathy (MSP)1,2,3.

引言核RNA结合蛋白（RBPs）与朊病毒样结构域（PrLD）的细胞质错位和聚集是神经退行性疾病的共同病理标志，包括肌萎缩侧索硬化症（ALS），额颞叶痴呆（FTD）和多系统蛋白病（MSP）1,2,3。

For example, the inclusion bodies of TAR DNA-binding protein 43 (TDP-43), fused in sarcoma (FUS), and heterogenous nuclear ribonucleoprotein A1 (hnRNPA1) are found in ALS and FTD patients4. These RBPs are predominately found in the nucleus, where they carry out their normal functions. However, mutations in their nuclear localization signal (NLS) and other environmental factors, such as stress, cause their mislocalization to the cytoplasm5,6,7,8.

例如，在ALS和FTD患者中发现了融合在肉瘤（FUS）中的TAR DNA结合蛋白43（TDP-43）和异源核糖核蛋白A1（hnRNPA1）的包涵体4。。然而，它们的核定位信号（NLS）和其他环境因素（例如压力）的突变会导致它们在细胞质中的错误定位5、6、7、8。

In the cytoplasm, these RBPs form aggregates through the interactions mediated by PrLD and other low complexity domains (LCDs)9,10,11,12, which can cause neurodegeneration in two ways: (i) the loss of function toxicity induced by nuclear depletion of RBPs and (ii) the gain of function toxicity induced by the aberrant assembly of RBPs in the cytoplasm.

在细胞质中，这些RBP通过PrLD和其他低复杂度结构域（LCD）9,10,11,12介导的相互作用形成聚集体，这可以通过两种方式引起神经退行性变：（i）RBP核耗竭引起的功能丧失毒性和（ii）RBP在细胞质中异常组装引起的功能获得毒性。

Therefore, a therapeutic strategy that restores the diffusive, functional state and nuclear localization of RBPs would rescue both the loss of function and the gain of function toxicity.Recently, we and others have shown that, besides their canonical function in nuclear transport, nuclear import receptors (NIRs) can function as molecular chaperones and protein disaggregators13,14,15,16.

因此，恢复RBP扩散，功能状态和核定位的治疗策略将挽救功能丧失和功能获得毒性。最近，我们和其他人已经表明，除了它们在核转运中的规范功能外，核输入受体（NIR）还可以作为分子伴侣和蛋白质解聚剂13,14,15,16。

Thus, the overexpression of NIRs can rescue the toxicity caused by RBP aggregation through simultaneously mitigating RBP aggregation and restoring their nuclear function. NIRs prevent and reverse the aggregation of their respective transport cargoes by binding to the nuclear localization signal .

因此，NIR的过表达可以通过同时减轻RBP聚集和恢复其核功能来挽救由RBP聚集引起的毒性。NIR通过与核定位信号结合来防止和逆转其各自运输货物的聚集。

FUSIBB holds a therapeutic potential to replace disease-causing endogenous FUS. In cultured cells, IBB is a highly efficient anti-aggregation signal, and FUSIBB can be transported and chaperoned by Imp β without Imp α. When cells are under oxidative stress by sodium arsenite treatment, FUSIBB remains nuclear and soluble, whereas WT FUS is assembled into stress granule64, indicating FUSIBB is more soluble than WT FUS.

FUSIBB具有替代致病内源性FUS的治疗潜力。在培养的细胞中，IBB是一种高效的抗聚集信号，FUSIBB可以被Impβ转运和伴侣化，而不需要Impα。当细胞通过亚砷酸钠处理处于氧化应激下时，FUSIBB保持核和可溶性，而WT FUS被组装成应激颗粒64，表明FUSIBB比WT FUS更易溶。

The higher solubility of FUSIBB leads to a strategy to replace aggregation-prone WT FUS with FUSIBB.This replacement strategy also exploits the autoregulatory feedback mechanism that controls FUS expression level; endogenous FUS expression is controlled by FUS protein binding to its pre-mRNA to prevent the accumulation of excess protein37,57,58.

FUSIBB的较高溶解度导致了一种用FUSIBB替代易聚集的WT FUS的策略。这种替代策略还利用了控制FUS表达水平的自动调节反馈机制；内源性FUS表达受FUS蛋白与其前mRNA结合的控制，以防止过量蛋白的积累37,57,58。

Indeed, a recent study showed that expressing WT FUS can rescue mutant FUS toxicity in mice expressing ALS-causing FUS mutant (i.e., FUSΔNLS) by reducing its expression level and replacing the mutant FUS65. For the majority of FTD patients, WT FUS, instead of a mutant FUS, is found in the inclusion body, which may result from disrupted Kap β2 function31,32,33,34,35,36.

实际上，最近的一项研究表明，表达WT FUS可以通过降低其表达水平并替代突变FUS65来挽救表达ALS引起的FUS突变体（即FUSΔNLS）的小鼠的突变FUS毒性。对于大多数FTD患者，在包涵体中发现了WT FUS而不是突变FUS，这可能是由于Kapβ2功能受损所致31,32,33,34,35,36。

In this case, replacing WT FUS with a more soluble FUS variant, such as the FUSIBB that employs an orthogonal transporter and chaperone other than Kap β2 (i.e., Imp β), will prevent further mislocalization of the disease-causing protein. As a proof of concept, our study showed that exogenously expressed FUSIBB can reduce the expression level of aggregation-prone, endogenous FUS.

在这种情况下，用更可溶性的FUS变体代替WT FUS，例如使用正交转运蛋白和Kapβ2以外的伴侣（即Impβ）的FUSBB，将防止致病蛋白的进一步错位。。

Three possible autoregulatory mechanisms have been proposed for FUS. First, binding of FUS protein to its pre-mRNA could lead to the splicing of exon 7, and the resulting abnormal ∆exon 7 FUS mRNA could then be degraded through nonsense-mediated mRNA decay37. Moreover, increas.

已经为FUS提出了三种可能的自动调节机制。首先，FUS蛋白与其前体mRNA的结合可能导致外显子7的剪接，然后产生的异常Δ外显子7 FUS mRNA可以通过无义介导的mRNA衰变降解37。此外，增加。

Data availability

数据可用性

All data generated in this study are available in the Article, Supplementary Information, and Source Data files. The FUSIBB-inducible HEK293 cells are available from the corresponding author upon request. Source data are provided with this paper.

本研究中产生的所有数据均可在文章，补充信息和源数据文件中找到。FUSIBB诱导型HEK293细胞可应要求从通讯作者处获得。本文提供了源数据。

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Download referencesAcknowledgementsWe thank Diane Merry for generously providing the Flp-In T-Rex 293 cells. L.G. was supported by Dr. Ralph and Marian Falk Medical Research Trust, Frick Foundation for ALS Research, the National Institute of General Medical Sciences grant R35GM138109, and the National Institute of Neurological Disorders and Stroke grant RF1NS121143.

下载参考文献致谢我们感谢Diane Merry慷慨提供Flp-In T-Rex 293细胞。五十、 G.得到了Ralph博士和Marian Falk医学研究信托基金会，弗里克ALS研究基金会，国家普通医学科学研究所拨款R35GM138109以及国家神经疾病和中风研究所拨款RF1NS121143的支持。

G.C. is supported by grants R35GM140733 and R21NS128396. J.D. was supported by NIH grant T32 GM144302.Author informationAuthor notesThese authors contributed equally: Miyuki Hayashi, Amandeep Girdhar, Ying-Hui Ko.Authors and AffiliationsDepartment of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, USAMiyuki Hayashi, Amandeep Girdhar, Kevin M.

G、 C.得到R35GM140733和R21NS128396赠款的支持。J、 D.得到了NIH资助T32 GM144302的支持。作者信息作者注意到这些作者做出了同样的贡献：Miyuki Hayashi，Amandeep Girdhar，Ying Hui Ko。作者和附属机构宾夕法尼亚州费城托马斯·杰斐逊大学生物化学与分子生物学系，USAMiyuki Hayashi，Amandeep Girdhar，Kevin M。

Kim, Jacquelyn A. DePierro, Joseph R. Buchler, Nikhita Arunprakash, Aditya Bajaj & Lin GuoDepartment of Biochemistry and Molecular Genetics, The University of Alabama at Birmingham, Birmingham, AL, USAYing-Hui Ko & Gino CingolaniDepartment of Neuroscience, Thomas Jefferson University, Philadelphia, PA, USAJoseph R.

Kim，Jacquelyn A.DePierro，Joseph R.Buchler，Nikhita Arunprakash，Aditya Bajaj＆Lin Guo阿拉巴马大学伯明翰分校生物化学与分子遗传学系，阿拉巴马州伯明翰，USAYing Hui Ko＆Gino Cingolani美国宾夕法尼亚州费城托马斯杰斐逊大学神经科学系Joseph R。

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PubMed Google ScholarContributionsM.H., A.G., and Y.H.K. performed the experimental studies and carried out the analysis. K.M.K., J.A.D., J.R.B., N.A., and A.B. performed the experimental studies. M.H., G.C., and L.G. wrote the manuscript. G.C. and L.G. supervised the work.Corresponding authorsCorrespondence to.

PubMed谷歌学术贡献。H、 ，A.G.和Y.H.K.进行了实验研究并进行了分析。K、 。M、 H.，G.C。和L.G.撰写了手稿。G、 C.和L.G.监督了这项工作。通讯作者通讯。

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Nature Communications thanks Yuh Min Chook and the other, anonymous, reviewers for their contribution to the peer review of this work. A peer review file is available.

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Reprints and permissionsAbout this articleCite this articleHayashi, M., Girdhar, A., Ko, YH. et al. Engineered NLS-chimera downregulates expression of aggregation-prone endogenous FUS.

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Nat Commun 15, 7887 (2024). https://doi.org/10.1038/s41467-024-52151-6Download citationReceived: 08 December 2023Accepted: 27 August 2024Published: 10 September 2024DOI: https://doi.org/10.1038/s41467-024-52151-6Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

《国家公社》157887（2024）。https://doi.org/10.1038/s41467-024-52151-6Download引文收到日期：2023年12月8日接受日期：2024年8月27日发布日期：2024年9月10日OI：https://doi.org/10.1038/s41467-024-52151-6Share本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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