无序连接体中的IGF2BP1磷酸化调节核糖核蛋白缩合物的形成和RNA代谢-动脉网

IGF2BP1 phosphorylation in the disordered linkers regulates ribonucleoprotein condensate formation and RNA metabolism

Nature 等信源发布 2024-10-20 13:07

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AbstractThe insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1) is a conserved RNA-binding protein that regulates RNA stability, localization and translation. IGF2BP1 is part of various ribonucleoprotein (RNP) condensates. However, the mechanism that regulates its assembly into condensates remains unknown.

摘要胰岛素样生长因子2 mRNA结合蛋白1（IGF2BP1）是一种保守的RNA结合蛋白，可调节RNA的稳定性，定位和翻译。IGF2BP1是各种核糖核蛋白（RNP）缩合物的一部分。然而，调节其组装成冷凝物的机制仍然未知。

By using proteomics, we demonstrate that phosphorylation of IGF2BP1 at S181 in a disordered linker is regulated in a stress-dependent manner. Phosphomimetic mutations in two disordered linkers, S181E and Y396E, modulate RNP condensate formation by IGF2BP1 without impacting its binding affinity for RNA.

通过使用蛋白质组学，我们证明了无序接头中S181处IGF2BP1的磷酸化以应激依赖性方式受到调节。两个无序接头S181E和Y396E中的磷酸化突变调节IGF2BP1形成的RNP冷凝物，而不影响其对RNA的结合亲和力。

Intriguingly, the S181E mutant, which lies in linker 1, impairs IGF2BP1 condensate formation in vitro and in cells, whereas a Y396E mutant in the second linker increases condensate size and dynamics. Structural approaches show that the first linker binds RNAs nonspecifically through its RGG/RG motif, an interaction weakened in the S181E mutant.

有趣的是，位于接头1中的S181E突变体会损害体外和细胞中IGF2BP1冷凝物的形成，而第二个接头中的Y396E突变体会增加冷凝物的大小和动力学。结构方法表明，第一个接头通过其RGG/RG基序非特异性结合RNA，这种相互作用在S181E突变体中减弱。

Notably, linker 2 interacts with IGF2BP1’s folded domains and these interactions are partially impaired in the Y396E mutant. Importantly, the phosphomimetic mutants impact IGF2BP1’s interaction with RNAs and remodel the transcriptome in cells. Our data reveal how phosphorylation modulates low-affinity interaction networks in disordered linkers to regulate RNP condensate formation and RNA metabolism..

值得注意的是，接头2与IGF2BP1的折叠结构域相互作用，并且这些相互作用在Y396E突变体中部分受损。重要的是，磷酸化模拟突变体影响IGF2BP1与RNA的相互作用并重塑细胞中的转录组。我们的数据揭示了磷酸化如何调节无序接头中的低亲和力相互作用网络，以调节RNP凝聚物的形成和RNA代谢。。

IntroductionRNA-binding proteins (RBPs) play important roles in post-transcriptional control of RNA1,2,3,4,5,6. IGF2BPs are a conserved family of RBPs that regulate RNA localization, translation and stability7,8,9,10,11. There are three IGF2BP paralogs (IGF2BP1-3) in mammals. Discovered in chicken embryos, IGF2BP1 was the founding member of the IGF2BP family12,13.

引言RNA结合蛋白（RBPs）在RNA1,2,3,4,5,6的转录后控制中起重要作用。IGF2BPs是一个保守的RBPs家族，可调节RNA的定位，翻译和稳定性7,8,9,10,11。哺乳动物中有三个IGF2BP旁系同源物（IGF2BP1-3）。在鸡胚中发现的IGF2BP1是IGF2BP家族的创始成员12,13。

IGF2BP1 is highly conserved in sequence and function across species (Supplemenetary Fig. 1A). It is highly expressed during mid to late embryogenesis and its expression decreases in adult tissues. In line with embryonic functions, Igf2bp1 knockout mice show developmental abnormalities14. However, IGF2BP1 expression is not restricted to early development, and it is detected later in differentiated gonads and the kidneys.

IGF2BP1在物种间的序列和功能上高度保守（补充图1A）。它在胚胎发生的中后期高度表达，在成体组织中表达降低。与胚胎功能一致，Igf2bp1基因敲除小鼠表现出发育异常14。然而，IGF2BP1的表达并不局限于早期发育，它在分化的性腺和肾脏中稍后被检测到。

Consistent with post-developmental functions, loss of IGF2BP1 in intestinal epithelial cells impairs intestinal homeostasis in adults15,16. IGF2BP1 is highly expressed in various tumors and its overexpression correlates with tumor aggressiveness9,17. Importantly, IGF2BP1 depletion impairs tumor growth, indicating that inhibition may have therapeutic potential in cancer cells18,19.

与发育后功能一致，肠上皮细胞中IGF2BP1的缺失会损害成年人的肠道稳态15,16。IGF2BP1在各种肿瘤中高度表达，其过表达与肿瘤侵袭性相关9,17。重要的是，IGF2BP1耗竭会损害肿瘤生长，表明抑制作用可能在癌细胞中具有治疗潜力18,19。

This link to disease underlines the importance of obtaining a mechanistic understanding of how IGF2BP1 exerts its function.IGF2BP1 is a canonical multi-domain RBP, which contains six RNA-binding domains: two RNA recognition motif (RRM) domains and four hnRNP K homology (KH) domains that are linked by two intrinsically disordered regions (Fig. 1A).

这种与疾病的联系强调了对IGF2BP1如何发挥其功能进行机械理解的重要性。IGF2BP1是一种典型的多结构域RBP，它包含六个RNA结合结构域：两个RNA识别基序（RRM）结构域和四个hnRNP K同源性（KH）结构域，它们由两个内在无序的区域连接（图1A）。

The KH domains are arranged into pseudodimers (KH1-2, and KH3-4). RNA recognition by IGF2BP1 is mediated by the KH domains, which interact with single-stranded RNAs through 4 nucleotide long recognition motifs20. In contrast, the RRM domains provide little specificity and pr.

KH结构域排列成假二聚体（KH1-2和KH3-4）。IGF2BP1的RNA识别由KH结构域介导，KH结构域通过4个核苷酸长的识别基序与单链RNA相互作用20。相反，RRM结构域几乎没有特异性和pr。

(3)

δH and δN are the chemical shift differences compared to the apo protein. Peaks unresolved in the concentrations used for the titration experiments were excluded from the analysis.Peaks were assigned by obtaining HNCO, HNCACO, HNCACB, HNCOCACB, HNCANNH and HNCOCANNH spectra of 300 µM 13C-15N-Linker 1 wild-type and 300 µM 13C-15N-Linker 2 wild-type and the respective HSQC spectra.

δH和δN是与载脂蛋白相比的化学位移差异。分析中排除了用于滴定实验的浓度中未解析的峰。通过获得300μM13C-15N-接头1野生型和300μM13C-15N-接头2野生型的HNCO，HNCACO，HNCACB，HNCOCACB，HNCANNH和HNCOCANNH光谱以及相应的HSQC光谱来分配峰。

Peak assignments were performed in CCPNMR. NMR assignments are available in Biological Magnetic Resonance Bank.Stress granule reconstitution in cell lysatesSplit-GFP tagged IGF2BP1 cells were seeded in a 15 cm dish and grown until they reached 90% confluency. Cells were washed with ice cold PBS, and harvested by scraping.

在CCPNMR中进行峰分配。NMR分配可在生物磁共振库中获得。细胞裂解物中的应激颗粒重建将裂解的GFP标记的IGF2BP1细胞接种在15厘米的培养皿中并生长直至达到90%汇合。用冰冷的PBS洗涤细胞，并通过刮擦收获。

Subsequently cells were centrifuged at 1123 g for 4 min. PBS was removed by aspiration, and cell pellet was flash-frozen. In order to lyse the cells, they were thawed and flash-frozen three times. Next, 500ul of lysis buffer, composed of 25 mM Tris pH 7, 0.5% NP-40, 1x Protease inhibitor cocktail, 2,5% murine RNAse inhibitor, 100 mM NaCl and 2 mM DTT, was added.

随后将细胞以1123g离心4分钟。通过抽吸除去PBS，并将细胞沉淀快速冷冻。为了裂解细胞，将它们解冻并速冻三次。接下来，加入500ul裂解缓冲液，其由25mM Tris pH 7,0.5%NP-40,1x蛋白酶抑制剂混合物，2.5%鼠RNAse抑制剂，100mM NaCl和2mM DTT组成。

After the addition of the lysis buffer, the cells were further resuspended using a 25 G needle 10 times. Next, two centrifugation steps ensued, first at 1500 g for 5 min, then 16,000 g for 8 min. Supernatants were transferred to a new tube, lysate concentration was measured using a BCA kit (ThermoFisher) and concentration was adjusted to 5 mg/ml using the lysate buffer.

加入裂解缓冲液后，使用25g针将细胞进一步重悬10次。接下来，进行两个离心步骤，首先以1500克离心5分钟，然后以16000克离心8分钟。将上清液转移到新管中，使用BCA试剂盒（ThermoFisher）测量裂解物浓度，并使用裂解物缓冲液将浓度调节至5毫克/毫升。

20uM of purified G3BP1 were added to induce LLPS followed by a 40 min incubation step. Afterwards, 5uM of mCherry-tagged IGF2BP1 was spiked in, gently mixed and incubated for 20 min. The µ-Slide Angiogenesis with ibiTreat 20 ul was used as an imaging vessel. Fluorescence recovery after photobleaching (FRAP) experiments were performed on .

加入20uM纯化的G3BP1以诱导LLP，然后进行40分钟的孵育步骤。然后，加入5uM mCherry标记的IGF2BP1，轻轻混合并孵育20分钟。用ibiTreat 20μl的μ-载玻片血管生成用作成像血管。进行光漂白（FRAP）实验后的荧光恢复。

Data availability

数据可用性

The source data are provided with this paper. All raw and processed sequencing data generated in this study have been deposited in the Gene Expression Omnibus database with the accession number GSE272875 (IGF2BP1 RNA-Seq and RIP-Seq data). The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium (http://proteomecentral.proteomexchange.org) via the PRIDE partner repository103 with the dataset identifier PXD045761 (mass spectrometry data of IGF2BP1 from HEK293T cells) and PXD056497 (mass spectrometry data of ProAlanase digested IGF2BP1 from HEK293T cells).

本文提供了源数据。本研究中产生的所有原始和处理过的测序数据均已保存在Gene Expression Omnibus数据库中，登录号为GSE272875（IGF2BP1 RNA-Seq和RIP-Seq数据）。质谱蛋白质组学数据已保存到ProteomeXchange Consortium(http://proteomecentral.proteomexchange.org)通过具有数据集标识符PXD045761（来自HEK293T细胞的IGF2BP1的质谱数据）和PXD056497（来自HEK293T细胞的丙氨酸蛋白酶消化的IGF2BP1的质谱数据）的PRIDE partner repository103。

The NMR signal assignments are deposited with BMRB ID 52567 (wild-type IGF2BP1 linker1 157-194) and 52568 (wild-type IGF2BP1 linker2 344-404) Source data are provided with this paper..

NMR信号分配存放在BMRB ID 52567（野生型IGF2BP1接头157-194）和52568（野生型IGF2BP1接头344-404）源数据中。。

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Download referencesAcknowledgementsWe are grateful to the late Thomas Peterbauer at the Max Perutz Labs Biooptics Light Microscopy Facility for his help and support. We thank Mila Asparuhova, Gizem Celebi and Isabell Niedermoser for their technical support and help. We appreciate the support from Julia Scholz in image analysis.

下载参考文献致谢我们感谢Max Perutz实验室生物光学光学光学显微镜设施已故的托马斯·彼得鲍尔的帮助和支持。我们感谢Mila Asparuhova、Gizem Celebi和Isabell Niedermoser的技术支持和帮助。我们感谢Julia Scholz在图像分析方面的支持。

We thank Gijs Versteeg and his lab for their help with lentiviral transduction and providing us with the expression plasmids. We thank Kitti Csalyi and Thomas Sauer at Max Perutz Labs Biooptics FACS facility for their help. We thank Georg Kontaxis for his continuing support with NMR measurements. Proteomics analyzes were performed by the Mass Spectrometry Facility at Max Perutz Labs using the VBCF instrument pool.

我们感谢Gijs Versteeg和他的实验室在慢病毒转导方面的帮助，并为我们提供了表达质粒。我们感谢Max Perutz实验室生物光学FACS设施的Kitti Csalyi和Thomas Sauer的帮助。我们感谢Georg Kontaxis对NMR测量的持续支持。。

We are grateful to Max Perutz Labs Mass spectrometry facility, Markus Hartl, Dorothea Anrather, Wei-qiang Chen and David Hollenstein for their help and support with measurements, data analyzes and experimental design. We are grateful to Thomas Leonard for his help with SEC-SAXS measurements and his invaluable input in data analyzes.

我们感谢Max Perutz实验室质谱设施，Markus Hartl，Dorothea Anrather，Wei qiang Chen和David Hollenstein在测量，数据分析和实验设计方面的帮助和支持。。

We thank Jeffrey A. Chao for providing us the MBP-tagged IGF2BP1 full-length. We thank Arthur Sedivy from the Vienna BioCenter ProTech Facility for his value support with DLS measurement and analysis. This research was funded in whole or in part by the Austrian Science Fund (FWF) [FWF-SFB F79 and FWF-W 1261] to GEK. For open access purposes, the author has applied a CC BY public copyright license to any author accepted manuscript version arising from this submission.E.S.

我们感谢Jeffrey A.Chao为我们提供了带有MBP标签的IGF2BP1全长。我们感谢维也纳生物中心ProTech设施的Arthur Sedivy在DLS测量和分析方面的价值支持。这项研究全部或部分由GEK的奥地利科学基金（FWF）[FWF-SFB F79和FWF-W 1261]资助。出于开放获取的目的，作者已将CC BY public copyright许可证应用于本次提交产生的任何作者接受的稿件版本。E、 S。

and R.C. acknowledge support and funding by the Frankfurt Institute of Advanced Studies, the LOEWE Center for Multiscale Modeling in Life Sciences of the state of Hesse, the Collaborative Research Center 1507 “Membrane-associ.

R.C.感谢法兰克福高等研究所，黑森州洛伊生命科学多尺度建模中心，1507“膜协会”合作研究中心的支持和资助。

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PubMed Google ScholarContributionsHH: Conceptualization. HH, ASA, AM, BB, ES and IN: Investigation, Methodology, Formal Analyzes and Visualization. TM, RC and GEK: Conceptualization, Funding acquisition and Supervision. HH and GEK wrote the original draft. All authors contributed to review and editing.Corresponding authorCorrespondence to.

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Reprints and permissionsAbout this articleCite this articleHornegger, H., Anisimova, A.S., Muratovic, A. et al. IGF2BP1 phosphorylation in the disordered linkers regulates ribonucleoprotein condensate formation and RNA metabolism.

转载和许可本文引用本文Hornegger，H.，Anisimova，A.S.，Muratovic，A。等人。无序接头中的IGF2BP1磷酸化调节核糖核蛋白凝聚物的形成和RNA代谢。

Nat Commun 15, 9054 (2024). https://doi.org/10.1038/s41467-024-53400-4Download citationReceived: 20 November 2023Accepted: 11 October 2024Published: 20 October 2024DOI: https://doi.org/10.1038/s41467-024-53400-4Share 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.

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