IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-60893-0.html
   My bibliography  Save this article

Decoding polyubiquitin regulation of KV7. 1 (KCNQ1) surface expression with engineered linkage-selective deubiquitinases

Author

Listed:
  • Sri Karthika Shanmugam

    (Columbia University Irving Medical Center)

  • Scott A. Kanner

    (Columbia University Irving Medical Center)

  • Xinle Zou

    (Columbia University Irving Medical Center)

  • Enoch Amarh

    (Columbia University Irving Medical Center)

  • Papiya Choudhury

    (Columbia University Irving Medical Center)

  • Rajesh Soni

    (Columbia University Irving Medical Center)

  • Robert S. Kass

    (Columbia University Irving Medical Center)

  • Henry M. Colecraft

    (Columbia University Irving Medical Center
    Columbia University Irving Medical Center)

Abstract

Polyubiquitin chain diversity generates a ‘ubiquitin code’ that universally regulates protein abundance, localization, and function. Functions of polyubiquitin diversity are mostly unknown, with lack of progress due to an inability to selectively tune protein polyubiquitin linkages in live cells. We develop linkage-selective engineered deubiquitinases (enDUBs) by fusing linkage-selective DUB catalytic domains to GFP-targeted nanobody and use them to investigate polyubiquitin linkage regulation of an ion channel, YFP-KCNQ1. YFP-KCNQ1 in HEK293 cells has polyubiquitin chains with K48/K63 linkages dominant. EnDUBs yield unique effects on channel surface abundance with a pattern indicating: K11 promotes ER retention/degradation, enhances endocytosis, and reduces recycling; K29/K33 promotes ER retention/degradation; K63 enhances endocytosis and reduces recycling; and K48 is necessary for forward trafficking. EnDUB effects differ in cardiomyocytes and on KCNQ1 disease mutants, emphasizing ubiquitin code mutability. The results reveal distinct polyubiquitin chains control different aspects of KCNQ1 abundance and subcellular localization and introduce linkage-selective enDUBs as potent tools to demystify the polyubiquitin code.

Suggested Citation

  • Sri Karthika Shanmugam & Scott A. Kanner & Xinle Zou & Enoch Amarh & Papiya Choudhury & Rajesh Soni & Robert S. Kass & Henry M. Colecraft, 2025. "Decoding polyubiquitin regulation of KV7. 1 (KCNQ1) surface expression with engineered linkage-selective deubiquitinases," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60893-0
    DOI: 10.1038/s41467-025-60893-0
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-60893-0
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-60893-0?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. Joseph L. Watson & David Juergens & Nathaniel R. Bennett & Brian L. Trippe & Jason Yim & Helen E. Eisenach & Woody Ahern & Andrew J. Borst & Robert J. Ragotte & Lukas F. Milles & Basile I. M. Wicky & , 2023. "De novo design of protein structure and function with RFdiffusion," Nature, Nature, vol. 620(7976), pages 1089-1100, August.
    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. Wei Yang & Derrick R. Hicks & Agnidipta Ghosh & Tristin A. Schwartze & Brian Conventry & Inna Goreshnik & Aza Allen & Samer F. Halabiya & Chan Johng Kim & Cynthia S. Hinck & David S. Lee & Asim K. Ber, 2025. "Design of high-affinity binders to immune modulating receptors for cancer immunotherapy," Nature Communications, Nature, vol. 16(1), pages 1-12, December.
    2. Arne Matthys & Jan Felix & Joao Paulo Portela Catani & Kenny Roose & Wim Nerinckx & Benthe Buyten & Daria Fijalkowska & Nico Callewaert & Savvas N. Savvides & Xavier Saelens, 2025. "Single-domain antibodies directed against hemagglutinin and neuraminidase protect against influenza B viruses," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    3. Ying Huang & Chenyang Xue & Ruiqian Bu & Cang Wu & Jiachen Li & Jinqiu Zhang & Jinyu Chen & Zhaoying Shi & Yonglong Chen & Yong Wang & Zhongmin Liu, 2024. "Inhibition and transport mechanisms of the ABC transporter hMRP5," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    4. Timothy Atkinson & Thomas D. Barrett & Scott Cameron & Bora Guloglu & Matthew Greenig & Charlie B. Tan & Louis Robinson & Alex Graves & Liviu Copoiu & Alexandre Laterre, 2025. "Protein sequence modelling with Bayesian flow networks," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
    5. Xiaorui Wang & Xiaodan Yin & Dejun Jiang & Huifeng Zhao & Zhenxing Wu & Odin Zhang & Jike Wang & Yuquan Li & Yafeng Deng & Huanxiang Liu & Pei Luo & Yuqiang Han & Tingjun Hou & Xiaojun Yao & Chang-Yu , 2024. "Multi-modal deep learning enables efficient and accurate annotation of enzymatic active sites," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    6. Simeon D. Castle & Michiel Stock & Thomas E. Gorochowski, 2024. "Engineering is evolution: a perspective on design processes to engineer biology," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    7. Daniel R. Fox & Kazem Asadollahi & Imogen Samuels & Bradley A. Spicer & Ashleigh Kropp & Christopher J. Lupton & Kevin Lim & Chunxiao Wang & Hari Venugopal & Marija Dramicanin & Gavin J. Knott & Rhys , 2025. "Inhibiting heme piracy by pathogenic Escherichia coli using de novo-designed proteins," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    8. Yash Chainani & Jacob Diaz & Margaret Guilarte-Silva & Vincent Blay & Quan Zhang & William Sprague & Keith E. J. Tyo & Linda J. Broadbelt & Aindrila Mukhopadhyay & Jay D. Keasling & Hector Garcia Mart, 2025. "Merging the computational design of chimeric type I polyketide synthases with enzymatic pathways for chemical biosynthesis," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    9. Aika Iwama & Ryoji Kise & Hiroaki Akasaka & Fumiya K. Sano & Hidetaka S. Oshima & Asuka Inoue & Wataru Shihoya & Osamu Nureki, 2024. "Structure and dynamics of the pyroglutamylated RF-amide peptide QRFP receptor GPR103," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    10. Wei Lu & Jixian Zhang & Weifeng Huang & Ziqiao Zhang & Xiangyu Jia & Zhenyu Wang & Leilei Shi & Chengtao Li & Peter G. Wolynes & Shuangjia Zheng, 2024. "DynamicBind: predicting ligand-specific protein-ligand complex structure with a deep equivariant generative model," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    11. Meghana Kshirsagar & Artur Meller & Ian R. Humphreys & Samuel Sledzieski & Yixi Xu & Rahul Dodhia & Eric Horvitz & Bonnie Berger & Gregory R. Bowman & Juan Lavista Ferres & David Baker & Minkyung Baek, 2025. "Rapid and accurate prediction of protein homo-oligomer symmetry using Seq2Symm," Nature Communications, Nature, vol. 16(1), pages 1-11, December.
    12. Laura Shub & Wenjin Liu & Georgios Skiniotis & Michael J. Keiser & Michael J. Robertson, 2025. "MIC: A deep learning tool for assigning ions and waters in cryo-EM and crystal structures," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
    13. Chase R. Freschlin & Sarah A. Fahlberg & Pete Heinzelman & Philip A. Romero, 2024. "Neural network extrapolation to distant regions of the protein fitness landscape," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    14. Isak S. Pretorius & Thomas A. Dixon & Michael Boers & Ian T. Paulsen & Daniel L. Johnson, 2025. "The coming wave of confluent biosynthetic, bioinformational and bioengineering technologies," Nature Communications, Nature, vol. 16(1), pages 1-8, December.
    15. Enrico Orsi & Lennart Schada von Borzyskowski & Stephan Noack & Pablo I. Nikel & Steffen N. Lindner, 2024. "Automated in vivo enzyme engineering accelerates biocatalyst optimization," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    16. Sophia Vincoff & Shrey Goel & Kseniia Kholina & Rishab Pulugurta & Pranay Vure & Pranam Chatterjee, 2025. "FusOn-pLM: a fusion oncoprotein-specific language model via adjusted rate masking," Nature Communications, Nature, vol. 16(1), pages 1-11, December.
    17. Lucien F. Krapp & Fernando A. Meireles & Luciano A. Abriata & Jean Devillard & Sarah Vacle & Maria J. Marcaida & Matteo Dal Peraro, 2024. "Context-aware geometric deep learning for protein sequence design," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    18. Chloe S. Adams & Hyojin Kim & Abigail E. Burtner & Dong Sun Lee & Craig Dobbins & Cameron Criswell & Brian Coventry & Adri Tran-Pearson & Ho Min Kim & Neil P. King, 2025. "De novo design of protein minibinder agonists of TLR3," Nature Communications, Nature, vol. 16(1), pages 1-11, December.
    19. Adibvafa Fallahpour & Vincent Gureghian & Guillaume J. Filion & Ariel B. Lindner & Amir Pandi, 2025. "CodonTransformer: a multispecies codon optimizer using context-aware neural networks," Nature Communications, Nature, vol. 16(1), pages 1-12, December.
    20. Simon d’Oelsnitz & Daniel J. Diaz & Wantae Kim & Daniel J. Acosta & Tyler L. Dangerfield & Mason W. Schechter & Matthew B. Minus & James R. Howard & Hannah Do & James M. Loy & Hal S. Alper & Y. Jessie, 2024. "Biosensor and machine learning-aided engineering of an amaryllidaceae enzyme," 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:16:y:2025:i:1:d:10.1038_s41467-025-60893-0. 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.