IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-58703-8.html
   My bibliography  Save this article

Spatial mechanisms of quality control during chaperone-mediated assembly of the proteasome

Author

Listed:
  • Eshita Das

    (University of Colorado Boulder)

  • Linh Le

    (University of Colorado Boulder)

  • Vladyslava Sokolova

    (University of Colorado Boulder
    Stony Brook University Medical School)

  • James D. Orth

    (University of Colorado Boulder)

  • Soyeon Park

    (University of Colorado Boulder)

Abstract

Cellular protein degradation requires a complex molecular machine, the proteasome. To mitigate the fundamental challenge of assembling the 66-subunit proteasome, cells utilize dedicated chaperones to order subunit addition. However, recent evidence suggests that proteasome assembly is not simply a series of subunit additions, but each step may be scrutinized so that only correct assembly events advance to proteasomes. Here, we find an unexpected mechanism of quality control (QC) during proteasome assembly—via the proteasomal nuclear localization signal (NLS). This mechanism specifically sequesters defective assembly intermediates to the nucleus, away from ongoing assembly in the cytoplasm, thereby antagonizing defective proteasome formation. This NLS, a bona fide proteasomal component, provides continuous surveillance throughout proteasome assembly. Even a single incorrect event activates spatial QC. Our findings illuminate a two-decade-old mystery in proteasome regulation; proteasomal NLSs, dispensable for proteasome localization, instead provide QC by compartmentalizing assembly defects to ensure that only correct proteasomes form.

Suggested Citation

  • Eshita Das & Linh Le & Vladyslava Sokolova & James D. Orth & Soyeon Park, 2025. "Spatial mechanisms of quality control during chaperone-mediated assembly of the proteasome," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58703-8
    DOI: 10.1038/s41467-025-58703-8
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-58703-8
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-58703-8?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. Melanie Almeida & Matthias Hinterndorfer & Hanna Brunner & Irina Grishkovskaya & Kashish Singh & Alexander Schleiffer & Julian Jude & Sumit Deswal & Robert Kalis & Milica Vunjak & Thomas Lendl & Richa, 2021. "AKIRIN2 controls the nuclear import of proteasomes in vertebrates," Nature, Nature, vol. 599(7885), pages 491-496, November.
    2. Yuko Hirano & Klavs B. Hendil & Hideki Yashiroda & Shun-ichiro Iemura & Ryoichi Nagane & Yusaku Hioki & Tohru Natsume & Keiji Tanaka & Shigeo Murata, 2005. "A heterodimeric complex that promotes the assembly of mammalian 20S proteasomes," Nature, Nature, vol. 437(7063), pages 1381-1385, October.
    3. Maximilian Seidel & Natalie Romanov & Agnieszka Obarska-Kosinska & Anja Becker & Nayara Trevisan Doimo de Azevedo & Jan Provaznik & Sankarshana R. Nagaraja & Jonathan J. M. Landry & Vladimir Benes & M, 2023. "Co-translational binding of importins to nascent proteins," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    4. Gabriel C. Lander & Eric Estrin & Mary E. Matyskiela & Charlene Bashore & Eva Nogales & Andreas Martin, 2012. "Complete subunit architecture of the proteasome regulatory particle," Nature, Nature, vol. 482(7384), pages 186-191, February.
    5. Soyeon Park & Jeroen Roelofs & Woong Kim & Jessica Robert & Marion Schmidt & Steven P. Gygi & Daniel Finley, 2009. "Hexameric assembly of the proteasomal ATPases is templated through their C termini," Nature, Nature, vol. 459(7248), pages 866-870, June.
    6. Jeroen Roelofs & Soyeon Park & Wilhelm Haas & Geng Tian & Fiona E. McAllister & Ying Huo & Byung-Hoon Lee & Fan Zhang & Yigong Shi & Steven P. Gygi & Daniel Finley, 2009. "Chaperone-mediated pathway of proteasome regulatory particle assembly," Nature, Nature, vol. 459(7248), pages 861-865, June.
    7. Chan-Gi Pack & Haruka Yukii & Akio Toh-e & Tai Kudo & Hikaru Tsuchiya & Ai Kaiho & Eri Sakata & Shigeo Murata & Hideyoshi Yokosawa & Yasushi Sako & Wolfgang Baumeister & Keiji Tanaka & Yasushi Saeki, 2014. "Quantitative live-cell imaging reveals spatio-temporal dynamics and cytoplasmic assembly of the 26S proteasome," Nature Communications, Nature, vol. 5(1), pages 1-10, May.
    8. Michael Groll & Lars Ditzel & Jan Löwe & Daniela Stock & Matthias Bochtler & Hans D. Bartunik & Robert Huber, 1997. "Structure of 20S proteasome from yeast at 2.4Å resolution," Nature, Nature, vol. 386(6624), pages 463-471, April.
    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. Nathan Jespersen & Kai Ehrenbolger & Rahel R. Winiger & Dennis Svedberg & Charles R. Vossbrinck & Jonas Barandun, 2022. "Structure of the reduced microsporidian proteasome bound by PI31-like peptides in dormant spores," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    2. Toshihiko Ogura, 2012. "High-Contrast Observation of Unstained Proteins and Viruses by Scanning Electron Microscopy," PLOS ONE, Public Library of Science, vol. 7(10), pages 1-7, October.
    3. Alexandra Shulkina & Kathrin Hacker & Julian F. Ehrmann & Valentina Budroni & Ariane Mandlbauer & Johannes Bock & Daniel B. Grabarczyk & Genevieve Edobor & Luisa Cochella & Tim Clausen & Gijs A. Verst, 2025. "TRIM52 maintains cellular fitness and is under tight proteolytic control by multiple giant E3 ligases," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    4. Yan Wang & Yi Wang & Tomohiro Iriki & Eiichi Hashimoto & Maki Inami & Sota Hashimoto & Ayako Watanabe & Hiroshi Takano & Ryo Motosugi & Shoshiro Hirayama & Hiroki Sugishita & Yukiko Gotoh & Ryoji Yao , 2025. "The DYT6 dystonia causative protein THAP1 is responsible for proteasome activity via PSMB5 transcriptional regulation," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
    5. Indrajit Sahu & Sachitanand M. Mali & Prasad Sulkshane & Cong Xu & Andrey Rozenberg & Roni Morag & Manisha Priyadarsini Sahoo & Sumeet K. Singh & Zhanyu Ding & Yifan Wang & Sharleen Day & Yao Cong & O, 2021. "The 20S as a stand-alone proteasome in cells can degrade the ubiquitin tag," Nature Communications, Nature, vol. 12(1), pages 1-21, December.
    6. Hanxiao Zhang & Chenyu Zhou & Zarith Mohammad & Jianhua Zhao, 2024. "Structural basis of human 20S proteasome biogenesis," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    7. Gang Xue & Jianing Xie & Matthias Hinterndorfer & Marko Cigler & Lara Dötsch & Hana Imrichova & Philipp Lampe & Xiufen Cheng & Soheila Rezaei Adariani & Georg E. Winter & Herbert Waldmann, 2023. "Discovery of a Drug-like, Natural Product-Inspired DCAF11 Ligand Chemotype," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    8. Edoardo Ratto & S. Roy Chowdhury & Nora S. Siefert & Martin Schneider & Marten Wittmann & Dominic Helm & Wilhelm Palm, 2022. "Direct control of lysosomal catabolic activity by mTORC1 through regulation of V-ATPase assembly," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    9. Darlene Fung & Aida Razi & Michael Pandos & Benjamin Velez & Erignacio Fermin Perez & Lea Adams & Shaun Rawson & Richard M. Walsh & John Hanna, 2025. "Evidence supporting a catalytic pentad mechanism for the proteasome and other N-terminal nucleophile enzymes," Nature Communications, Nature, vol. 16(1), pages 1-12, December.
    10. Kwadwo A. Opoku-Nsiah & Andres H. Pena & Sarah K. Williams & Nikita Chopra & Andrej Sali & Gabriel C. Lander & Jason E. Gestwicki, 2022. "The YΦ motif defines the structure-activity relationships of human 20S proteasome activators," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    11. Lei Pang & Yuanzhi Huang & Yilin He & Dong Jiang & Ruixi Li, 2025. "The adaptor protein AP-3β disassembles heat-induced stress granules via 19S regulatory particle in Arabidopsis," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    12. Jingyu Zhan & Allison Zeher & Rick Huang & Wai Kwan Tang & Lisa M. Jenkins & Di Xia, 2024. "Conformations of Bcs1L undergoing ATP hydrolysis suggest a concerted translocation mechanism for folded iron-sulfur protein substrate," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    13. Nobuo Kanazawa & Hiroaki Hemmi & Noriko Kinjo & Hidenori Ohnishi & Jun Hamazaki & Hiroyuki Mishima & Akira Kinoshita & Tsunehiro Mizushima & Satoru Hamada & Kazuya Hamada & Norio Kawamoto & Saori Kado, 2021. "Heterozygous missense variant of the proteasome subunit β-type 9 causes neonatal-onset autoinflammation and immunodeficiency," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    14. Chrysanthi Kagiou & Jose A. Cisneros & Jakob Farnung & Joanna Liwocha & Fabian Offensperger & Kevin Dong & Ka Yang & Gary Tin & Christina S. Horstmann & Matthias Hinterndorfer & Joao A. Paulo & Natali, 2024. "Alkylamine-tethered molecules recruit FBXO22 for targeted protein degradation," 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_s41467-025-58703-8. 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.