IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-52149-0.html
   My bibliography  Save this article

Human cell surface-AAV interactomes identify LRP6 as blood-brain barrier transcytosis receptor and immune cytokine IL3 as AAV9 binder

Author

Listed:
  • Timothy F. Shay

    (California Institute of Technology)

  • Seongmin Jang

    (California Institute of Technology)

  • Tyler J. Brittain

    (California Institute of Technology)

  • Xinhong Chen

    (California Institute of Technology)

  • Beth Walker

    (Charles River Laboratories)

  • Claire Tebbutt

    (Charles River Laboratories)

  • Yujie Fan

    (California Institute of Technology)

  • Damien A. Wolfe

    (California Institute of Technology)

  • Cynthia M. Arokiaraj

    (California Institute of Technology)

  • Erin E. Sullivan

    (California Institute of Technology)

  • Xiaozhe Ding

    (California Institute of Technology)

  • Ting-Yu Wang

    (California Institute of Technology)

  • Yaping Lei

    (California Institute of Technology)

  • Miguel R. Chuapoco

    (California Institute of Technology)

  • Tsui-Fen Chou

    (California Institute of Technology)

  • Viviana Gradinaru

    (California Institute of Technology)

Abstract

Adeno-associated viruses (AAVs) are foundational gene delivery tools for basic science and clinical therapeutics. However, lack of mechanistic insight, especially for engineered vectors created by directed evolution, can hamper their application. Here, we adapt an unbiased human cell microarray platform to determine the extracellular and cell surface interactomes of natural and engineered AAVs. We identify a naturally-evolved and serotype-specific interaction between the AAV9 capsid and human interleukin 3 (IL3), with possible roles in host immune modulation, as well as lab-evolved low-density lipoprotein receptor-related protein 6 (LRP6) interactions specific to engineered capsids with enhanced blood-brain barrier crossing in non-human primates after intravenous administration. The unbiased cell microarray screening approach also allows us to identify off-target tissue binding interactions of engineered brain-enriched AAV capsids that may inform vectors’ peripheral organ tropism and side effects. Our cryo-electron tomography and AlphaFold modeling of capsid-interactor complexes reveal LRP6 and IL3 binding sites. These results allow confident application of engineered AAVs in diverse organisms and unlock future target-informed engineering of improved viral and non-viral vectors for non-invasive therapeutic delivery to the brain.

Suggested Citation

  • Timothy F. Shay & Seongmin Jang & Tyler J. Brittain & Xinhong Chen & Beth Walker & Claire Tebbutt & Yujie Fan & Damien A. Wolfe & Cynthia M. Arokiaraj & Erin E. Sullivan & Xiaozhe Ding & Ting-Yu Wang , 2024. "Human cell surface-AAV interactomes identify LRP6 as blood-brain barrier transcytosis receptor and immune cytokine IL3 as AAV9 binder," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52149-0
    DOI: 10.1038/s41467-024-52149-0
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-52149-0
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-024-52149-0?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Jinuk Kim & Wonhee Han & Taeyong Park & Eun Jin Kim & Injin Bang & Hyun Sik Lee & Yejin Jeong & Kyeonghwan Roh & Jeesoo Kim & Jong-Seo Kim & Chanhee Kang & Chaok Seok & Jin-Kwan Han & Hee-Jung Choi, 2020. "Sclerostin inhibits Wnt signaling through tandem interaction with two LRP6 ectodomains," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    2. Francisco J. Garcia & Na Sun & Hyeseung Lee & Brianna Godlewski & Hansruedi Mathys & Kyriaki Galani & Blake Zhou & Xueqiao Jiang & Ayesha P. Ng & Julio Mantero & Li-Huei Tsai & David A. Bennett & Must, 2022. "Single-cell dissection of the human brain vasculature," Nature, Nature, vol. 603(7903), pages 893-899, March.
    3. Koji Hase & Kazuya Kawano & Tomonori Nochi & Gemilson Soares Pontes & Shinji Fukuda & Masashi Ebisawa & Kazunori Kadokura & Toru Tobe & Yumiko Fujimura & Sayaka Kawano & Atsuko Yabashi & Satoshi Wagur, 2009. "Uptake through glycoprotein 2 of FimH+ bacteria by M cells initiates mucosal immune response," Nature, Nature, vol. 462(7270), pages 226-230, November.
    4. Sophie E. Broughton & Timothy R. Hercus & Tracy L. Nero & Winnie L. Kan & Emma F. Barry & Mara Dottore & Karen S. Cheung Tung Shing & Craig J. Morton & Urmi Dhagat & Matthew P. Hardy & Nicholas J. Wil, 2018. "A dual role for the N-terminal domain of the IL-3 receptor in cell signalling," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    5. Fan Liu & Philip Lössl & Richard Scheltema & Rosa Viner & Albert J. R. Heck, 2017. "Optimized fragmentation schemes and data analysis strategies for proteome-wide cross-link identification," Nature Communications, Nature, vol. 8(1), pages 1-8, August.
    6. Andrew C. Yang & Ryan T. Vest & Fabian Kern & Davis P. Lee & Maayan Agam & Christina A. Maat & Patricia M. Losada & Michelle B. Chen & Nicholas Schaum & Nathalie Khoury & Angus Toland & Kruti Calcutta, 2022. "A human brain vascular atlas reveals diverse mediators of Alzheimer’s risk," Nature, Nature, vol. 603(7903), pages 885-892, March.
    7. S. Pillay & N. L. Meyer & A. S. Puschnik & O. Davulcu & J. Diep & Y. Ishikawa & L. T. Jae & J. E. Wosen & C. M. Nagamine & M. S. Chapman & J. E. Carette, 2016. "An essential receptor for adeno-associated virus infection," Nature, Nature, vol. 530(7588), pages 108-112, February.
    8. Kylie S. Chew & Robert C. Wells & Arash Moshkforoush & Darren Chan & Kendra J. Lechtenberg & Hai L. Tran & Johann Chow & Do Jin Kim & Yaneth Robles-Colmenares & Devendra B. Srivastava & Raymond K. Ton, 2023. "Author Correction: CD98hc is a target for brain delivery of biotherapeutics," Nature Communications, Nature, vol. 14(1), pages 1-1, December.
    9. Xinhong Chen & Damien A. Wolfe & Dhanesh Sivadasan Bindu & Mengying Zhang & Naz Taskin & David Goertsen & Timothy F. Shay & Erin E. Sullivan & Sheng-Fu Huang & Sripriya Ravindra Kumar & Cynthia M. Aro, 2023. "Functional gene delivery to and across brain vasculature of systemic AAVs with endothelial-specific tropism in rodents and broad tropism in primates," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    10. Kylie S. Chew & Robert C. Wells & Arash Moshkforoush & Darren Chan & Kendra J. Lechtenberg & Hai L. Tran & Johann Chow & Do Jin Kim & Yaneth Robles-Colmenares & Devendra B. Srivastava & Raymond K. Ton, 2023. "CD98hc is a target for brain delivery of biotherapeutics," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    11. Cameron S. McAlpine & Joseph Park & Ana Griciuc & Eunhee Kim & Se Hoon Choi & Yoshiko Iwamoto & Máté G. Kiss & Kathleen A. Christie & Claudio Vinegoni & Wolfram C. Poller & John E. Mindur & Christophe, 2021. "Astrocytic interleukin-3 programs microglia and limits Alzheimer’s disease," Nature, Nature, vol. 595(7869), pages 701-706, July.
    12. Joshua D. Backman & Alexander H. Li & Anthony Marcketta & Dylan Sun & Joelle Mbatchou & Michael D. Kessler & Christian Benner & Daren Liu & Adam E. Locke & Suganthi Balasubramanian & Ashish Yadav & Ni, 2021. "Exome sequencing and analysis of 454,787 UK Biobank participants," Nature, Nature, vol. 599(7886), pages 628-634, November.
    13. Jai Woong Seo & Elizabeth S. Ingham & Lisa Mahakian & Spencer Tumbale & Bo Wu & Sadaf Aghevlian & Shahin Shams & Mo Baikoghli & Poorva Jain & Xiaozhe Ding & Nick Goeden & Tatyana Dobreva & Nicholas C., 2020. "Positron emission tomography imaging of novel AAV capsids maps rapid brain accumulation," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    14. Louise Turner & Thomas Lavstsen & Sanne S. Berger & Christian W. Wang & Jens E. V. Petersen & Marion Avril & Andrew J. Brazier & Jim Freeth & Jakob S. Jespersen & Morten A. Nielsen & Pamela Magistrado, 2013. "Severe malaria is associated with parasite binding to endothelial protein C receptor," Nature, Nature, vol. 498(7455), pages 502-505, June.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Özkan İş & Xue Wang & Joseph S. Reddy & Yuhao Min & Elanur Yilmaz & Prabesh Bhattarai & Tulsi Patel & Jeremiah Bergman & Zachary Quicksall & Michael G. Heckman & Frederick Q. Tutor-New & Birsen Can De, 2024. "Gliovascular transcriptional perturbations in Alzheimer’s disease reveal molecular mechanisms of blood brain barrier dysfunction," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
    2. Nicola A. Kearns & Artemis Iatrou & Daniel J. Flood & Sashini Tissera & Zachary M. Mullaney & Jishu Xu & Chris Gaiteri & David A. Bennett & Yanling Wang, 2023. "Dissecting the human leptomeninges at single-cell resolution," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    3. Paula Punzon-Jimenez & Alba Machado-Lopez & Raul Perez-Moraga & Jaime Llera-Oyola & Daniela Grases & Marta Galvez-Viedma & Mustafa Sibai & Elena Satorres-Perez & Susana Lopez-Agullo & Rafael Badenes &, 2024. "Effect of aging on the human myometrium at single-cell resolution," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    4. Stergios Tsartsalis & Hannah Sleven & Nurun Fancy & Frank Wessely & Amy M. Smith & Nanet Willumsen & To Ka Dorcas Cheung & Michal J. Rokicki & Vicky Chau & Eseoghene Ifie & Combiz Khozoie & Olaf Ansor, 2024. "A single nuclear transcriptomic characterisation of mechanisms responsible for impaired angiogenesis and blood-brain barrier function in Alzheimer’s disease," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    5. Jan Marten Schmidt & Ran Yang & Ashish Kumar & Olivia Hunker & Jan Seebacher & Franziska Bleichert, 2022. "A mechanism of origin licensing control through autoinhibition of S. cerevisiae ORC·DNA·Cdc6," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    6. Natalie DeForest & Yuqi Wang & Zhiyi Zhu & Jacqueline S. Dron & Ryan Koesterer & Pradeep Natarajan & Jason Flannick & Tiffany Amariuta & Gina M. Peloso & Amit R. Majithia, 2024. "Genome-wide discovery and integrative genomic characterization of insulin resistance loci using serum triglycerides to HDL-cholesterol ratio as a proxy," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    7. Dick Schijven & Sourena Soheili-Nezhad & Simon E. Fisher & Clyde Francks, 2024. "Exome-wide analysis implicates rare protein-altering variants in human handedness," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    8. Jasjot Singh & Hadeer Elhabashy & Pathma Muthukottiappan & Markus Stepath & Martin Eisenacher & Oliver Kohlbacher & Volkmar Gieselmann & Dominic Winter, 2022. "Cross-linking of the endolysosomal system reveals potential flotillin structures and cargo," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    9. Mit Shah & Marco H. A. Inácio & Chang Lu & Pierre-Raphaël Schiratti & Sean L. Zheng & Adam Clement & Antonio Marvao & Wenjia Bai & Andrew P. King & James S. Ware & Martin R. Wilkins & Johanna Mielke &, 2023. "Environmental and genetic predictors of human cardiovascular ageing," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    10. Matthew Tegtmeyer & Jatin Arora & Samira Asgari & Beth A. Cimini & Ajay Nadig & Emily Peirent & Dhara Liyanage & Gregory P. Way & Erin Weisbart & Aparna Nathan & Tiffany Amariuta & Kevin Eggan & Marzi, 2024. "High-dimensional phenotyping to define the genetic basis of cellular morphology," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    11. Erik Schoenmakers & Federica Marelli & Helle F. Jørgensen & W. Edward Visser & Carla Moran & Stefan Groeneweg & Carolina Avalos & Sean J. Jurgens & Nichola Figg & Alison Finigan & Neha Wali & Maura Ag, 2023. "Selenoprotein deficiency disorder predisposes to aortic aneurysm formation," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    12. Xinhong Chen & Damien A. Wolfe & Dhanesh Sivadasan Bindu & Mengying Zhang & Naz Taskin & David Goertsen & Timothy F. Shay & Erin E. Sullivan & Sheng-Fu Huang & Sripriya Ravindra Kumar & Cynthia M. Aro, 2023. "Functional gene delivery to and across brain vasculature of systemic AAVs with endothelial-specific tropism in rodents and broad tropism in primates," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    13. Xiaoyi Raymond Gao & Marion Chiariglione & Alexander J. Arch, 2022. "Whole-exome sequencing study identifies rare variants and genes associated with intraocular pressure and glaucoma," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    14. Nazia Pathan & Wei Q. Deng & Matteo Di Scipio & Mohammad Khan & Shihong Mao & Robert W. Morton & Ricky Lali & Marie Pigeyre & Michael R. Chong & Guillaume Paré, 2024. "A method to estimate the contribution of rare coding variants to complex trait heritability," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    15. Hyun-Sik Yang & Ling Teng & Daniel Kang & Vilas Menon & Tian Ge & Hilary K. Finucane & Aaron P. Schultz & Michael Properzi & Hans-Ulrich Klein & Lori B. Chibnik & Julie A. Schneider & David A. Bennett, 2023. "Cell-type-specific Alzheimer’s disease polygenic risk scores are associated with distinct disease processes in Alzheimer’s disease," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    16. Naman S. Shetty & Mokshad Gaonkar & Nirav Patel & Akhil Pampana & Nehal Vekariya & Peng Li & Garima Arora & Pankaj Arora, 2024. "Determinants of transthyretin levels and their association with adverse clinical outcomes among UK Biobank participants," Nature Communications, Nature, vol. 15(1), pages 1-7, December.
    17. Ryan G. Lim & Osama Al-Dalahmah & Jie Wu & Maxwell P. Gold & Jack C. Reidling & Guomei Tang & Miriam Adam & David K. Dansu & Hye-Jin Park & Patrizia Casaccia & Ricardo Miramontes & Andrea M. Reyes-Ort, 2022. "Huntington disease oligodendrocyte maturation deficits revealed by single-nucleus RNAseq are rescued by thiamine-biotin supplementation," Nature Communications, Nature, vol. 13(1), pages 1-23, December.
    18. Aimee M. Deaton & Aditi Dubey & Lucas D. Ward & Peter Dornbos & Jason Flannick & Elaine Yee & Simina Ticau & Leila Noetzli & Margaret M. Parker & Rachel A. Hoffing & Carissa Willis & Mollie E. Plekan , 2022. "Rare loss of function variants in the hepatokine gene INHBE protect from abdominal obesity," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    19. Cathy Pichol-Thievend & Oceane Anezo & Aafrin M. Pettiwala & Guillaume Bourmeau & Remi Montagne & Anne-Marie Lyne & Pierre-Olivier Guichet & Pauline Deshors & Alberto Ballestín & Benjamin Blanchard & , 2024. "VC-resist glioblastoma cell state: vessel co-option as a key driver of chemoradiation resistance," Nature Communications, Nature, vol. 15(1), pages 1-27, December.
    20. Gerry Q Tonkin-Hill & Leily Trianty & Rintis Noviyanti & Hanh H T Nguyen & Boni F Sebayang & Daniel A Lampah & Jutta Marfurt & Simon A Cobbold & Janavi S Rambhatla & Malcolm J McConville & Stephen J R, 2018. "The Plasmodium falciparum transcriptome in severe malaria reveals altered expression of genes involved in important processes including surface antigen–encoding var genes," PLOS Biology, Public Library of Science, vol. 16(3), pages 1-40, March.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52149-0. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.