IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-023-44624-x.html
   My bibliography  Save this article

The low-density lipoprotein receptor promotes infection of multiple encephalitic alphaviruses

Author

Listed:
  • Hongming Ma

    (Washington University School of Medicine)

  • Lucas J. Adams

    (Washington University School of Medicine)

  • Saravanan Raju

    (Washington University School of Medicine
    Washington University School of Medicine)

  • Alan Sariol

    (Washington University School of Medicine)

  • Natasha M. Kafai

    (Washington University School of Medicine)

  • Hana Janova

    (Washington University School of Medicine
    Washington University School of Medicine)

  • William B. Klimstra

    (The University of Pittsburgh)

  • Daved H. Fremont

    (Washington University School of Medicine
    Washington University School of Medicine
    Washington University School of Medicine)

  • Michael S. Diamond

    (Washington University School of Medicine
    Washington University School of Medicine
    Washington University School of Medicine
    Washington University School of Medicine)

Abstract

Members of the low-density lipoprotein receptor (LDLR) family, including LDLRAD3, VLDLR, and ApoER2, were recently described as entry factors for different alphaviruses. However, based on studies with gene edited cells and knockout mice, blockade or abrogation of these receptors does not fully inhibit alphavirus infection, indicating the existence of additional uncharacterized entry factors. Here, we perform a CRISPR-Cas9 genome-wide loss-of-function screen in mouse neuronal cells with a chimeric alphavirus expressing the Eastern equine encephalitis virus (EEEV) structural proteins and identify LDLR as a candidate receptor. Expression of LDLR on the surface of neuronal or non-neuronal cells facilitates binding and infection of EEEV, Western equine encephalitis virus, and Semliki Forest virus. Domain mapping and binding studies reveal a low-affinity interaction with LA domain 3 (LA3) that can be enhanced by concatenation of LA3 repeats. Soluble decoy proteins with multiple LA3 repeats inhibit EEEV infection in cell culture and in mice. Our results establish LDLR as a low-affinity receptor for multiple alphaviruses and highlight a possible path for developing inhibitors that could mitigate infection and disease.

Suggested Citation

  • Hongming Ma & Lucas J. Adams & Saravanan Raju & Alan Sariol & Natasha M. Kafai & Hana Janova & William B. Klimstra & Daved H. Fremont & Michael S. Diamond, 2024. "The low-density lipoprotein receptor promotes infection of multiple encephalitic alphaviruses," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-023-44624-x
    DOI: 10.1038/s41467-023-44624-x
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-44624-x
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-023-44624-x?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. Jovan Nikolic & Laura Belot & Hélène Raux & Pierre Legrand & Yves Gaudin & Aurélie Albertini, 2018. "Structural basis for the recognition of LDL-receptor family members by VSV glycoprotein," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    2. Katherine Basore & Hongming Ma & Natasha M. Kafai & Samantha Mackin & Arthur S. Kim & Christopher A. Nelson & Michael S. Diamond & Daved H. Fremont, 2021. "Structure of Venezuelan equine encephalitis virus in complex with the LDLRAD3 receptor," Nature, Nature, vol. 598(7882), pages 672-676, October.
    3. Hongming Ma & Arthur S. Kim & Natasha M. Kafai & James T. Earnest & Aadit P. Shah & James Brett Case & Katherine Basore & Theron C. Gilliland & Chengqun Sun & Christopher A. Nelson & Larissa B. Thackr, 2020. "LDLRAD3 is a receptor for Venezuelan equine encephalitis virus," Nature, Nature, vol. 588(7837), pages 308-314, December.
    4. Deborah Fass & Stephen Blacklow & Peter S. Kim & James M. Berger, 1997. "Molecular basis of familial hypercholesterolaemia from structure of LDL receptor module," Nature, Nature, vol. 388(6643), pages 691-693, August.
    5. Rong Zhang & Arthur S. Kim & Julie M. Fox & Sharmila Nair & Katherine Basore & William B. Klimstra & Rebecca Rimkunas & Rachel H. Fong & Hueylie Lin & Subhajit Poddar & James E. Crowe & Benjamin J. Do, 2018. "Mxra8 is a receptor for multiple arthritogenic alphaviruses," Nature, Nature, vol. 557(7706), pages 570-574, May.
    6. Bingting Ma & Cuiqing Huang & Jun Ma & Ye Xiang & Xinzheng Zhang, 2021. "Structure of Venezuelan equine encephalitis virus with its receptor LDLRAD3," Nature, Nature, vol. 598(7882), pages 677-681, October.
    7. Lars E. Clark & Sarah A. Clark & ChieYu Lin & Jianying Liu & Adrian Coscia & Katherine G. Nabel & Pan Yang & Dylan V. Neel & Hyo Lee & Vesna Brusic & Iryna Stryapunina & Kenneth S. Plante & Asim A. Ah, 2022. "VLDLR and ApoER2 are receptors for multiple alphaviruses," Nature, Nature, vol. 602(7897), pages 475-480, February.
    Full references (including those not matched with items on IDEAS)

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Ningning Wang & Andres Merits & Michael Veit & Laura Sandra Lello & Shuhan Kong & Houqi Jiao & Jie Chen & Yu Wang & Georgi Dobrikov & Félix A. Rey & Shuo Su, 2024. "LDL receptor in alphavirus entry: structural analysis and implications for antiviral therapy," Nature Communications, Nature, vol. 15(1), pages 1-7, December.

    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. Pan Yang & Wanyu Li & Xiaoyi Fan & Junhua Pan & Colin J. Mann & Haley Varnum & Lars E. Clark & Sarah A. Clark & Adrian Coscia & Himanish Basu & Katherine Nabel Smith & Vesna Brusic & Jonathan Abraham, 2024. "Structural basis for VLDLR recognition by eastern equine encephalitis virus," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    2. Xiaofeng Zhai & Xiaoling Li & Michael Veit & Ningning Wang & Yu Wang & Andres Merits & Zhiwen Jiang & Yan Qin & Xiaoguang Zhang & Kaili Qi & Houqi Jiao & Wan-Ting He & Ye Chen & Yang Mao & Shuo Su, 2024. "LDLR is used as a cell entry receptor by multiple alphaviruses," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    3. Duanfang Cao & Bingting Ma & Ziyi Cao & Xiaoyu Xu & Xinzheng Zhang & Ye Xiang, 2024. "The receptor VLDLR binds Eastern Equine Encephalitis virus through multiple distinct modes," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    4. Ningning Wang & Andres Merits & Michael Veit & Laura Sandra Lello & Shuhan Kong & Houqi Jiao & Jie Chen & Yu Wang & Georgi Dobrikov & Félix A. Rey & Shuo Su, 2024. "LDL receptor in alphavirus entry: structural analysis and implications for antiviral therapy," Nature Communications, Nature, vol. 15(1), pages 1-7, December.
    5. Maureen Ritter & Lola Canus & Anupriya Gautam & Thomas Vallet & Li Zhong & Alexandre Lalande & Bertrand Boson & Apoorv Gandhi & Sergueï Bodoirat & Julien Burlaud-Gaillard & Natalia Freitas & Philippe , 2024. "The low-density lipoprotein receptor and apolipoprotein E associated with CCHFV particles mediate CCHFV entry into cells," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    6. Li Guo & Cheng Hu & Yang Liu & Xiaoyu Chen & Deli Song & Runling Shen & Zhanzhen Liu & Xudong Jia & Qinfen Zhang & Yuanzhu Gao & Zhezhi Deng & Tao Zuo & Jun Hu & Wenbo Zhu & Jing Cai & Guangmei Yan & , 2023. "Directed natural evolution generates a next-generation oncolytic virus with a high potency and safety profile," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    7. Daniel Strebinger & Chris J. Frangieh & Mirco J. Friedrich & Guilhem Faure & Rhiannon K. Macrae & Feng Zhang, 2023. "Cell type-specific delivery by modular envelope design," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    8. Wern Hann Ng & Xiang Liu & Zheng L. Ling & Camilla N. O. Santos & Lucas S. Magalhães & Andrew J. Kueh & Marco J. Herold & Adam Taylor & Joseph R. Freitas & Sandra Koit & Sainan Wang & Andrew R. Lloyd , 2023. "FHL1 promotes chikungunya and o’nyong-nyong virus infection and pathogenesis with implications for alphavirus vaccine design," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    9. Wenjie Qiao & Christopher M. Richards & Youlim Kim & James R. Zengel & Siyuan Ding & Harry B. Greenberg & Jan E. Carette, 2024. "MYADM binds human parechovirus 1 and is essential for viral entry," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

    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_s41467-023-44624-x. 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.