IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-40952-0.html
   My bibliography  Save this article

DNAJA2 deficiency activates cGAS-STING pathway via the induction of aberrant mitosis and chromosome instability

Author

Listed:
  • Yaping Huang

    (University of Texas Southwestern Medical Center)

  • Changzheng Lu

    (University of Texas Southwestern Medical Center
    Shenzhen Bay Laboratory)

  • Hanzhi Wang

    (University of Texas Southwestern Medical Center)

  • Liya Gu

    (University of Texas Southwestern Medical Center)

  • Yang-Xin Fu

    (University of Texas Southwestern Medical Center
    Tsinghua University School of Medicine)

  • Guo-Min Li

    (University of Texas Southwestern Medical Center
    Chinese Institutes for Medical Research)

Abstract

Molecular chaperone HSP70s are attractive targets for cancer therapy, but their substrate broadness and functional non-specificity have limited their role in therapeutical success. Functioning as HSP70’s cochaperones, HSP40s determine the client specificity of HSP70s, and could be better targets for cancer therapy. Here we show that tumors defective in HSP40 member DNAJA2 are benefitted from immune-checkpoint blockade (ICB) therapy. Mechanistically, DNAJA2 maintains centrosome homeostasis by timely degrading key centriolar satellite proteins PCM1 and CEP290 via HSC70 chaperone-mediated autophagy (CMA). Tumor cells depleted of DNAJA2 or CMA factor LAMP2A exhibit elevated levels of centriolar satellite proteins, which causes aberrant mitosis characterized by abnormal spindles, chromosome missegregation and micronuclei formation. This activates the cGAS-STING pathway to enhance ICB therapy response in tumors derived from DNAJA2-deficient cells. Our study reveals a role for DNAJA2 to regulate mitotic division and chromosome stability and suggests DNAJA2 as a potential target to enhance cancer immunotherapy, thereby providing strategies to advance HSPs-based cancer therapy.

Suggested Citation

  • Yaping Huang & Changzheng Lu & Hanzhi Wang & Liya Gu & Yang-Xin Fu & Guo-Min Li, 2023. "DNAJA2 deficiency activates cGAS-STING pathway via the induction of aberrant mitosis and chromosome instability," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40952-0
    DOI: 10.1038/s41467-023-40952-0
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-40952-0
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-023-40952-0?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. Ji Li & Vincenzo D’Angiolella & E. Scott Seeley & Sehyun Kim & Tetsuo Kobayashi & Wenxiang Fu & Eric I. Campos & Michele Pagano & Brian David Dynlacht, 2013. "USP33 regulates centrosome biogenesis via deubiquitination of the centriolar protein CP110," Nature, Nature, vol. 495(7440), pages 255-259, March.
    2. Søs Grønbæk Holdgaard & Valentina Cianfanelli & Emanuela Pupo & Matteo Lambrughi & Michal Lubas & Julie C. Nielsen & Susana Eibes & Emiliano Maiani & Lea M. Harder & Nicole Wesch & Mads Møller Foged &, 2019. "Selective autophagy maintains centrosome integrity and accurate mitosis by turnover of centriolar satellites," Nature Communications, Nature, vol. 10(1), pages 1-19, December.
    3. Karen J. Mackenzie & Paula Carroll & Carol-Anne Martin & Olga Murina & Adeline Fluteau & Daniel J. Simpson & Nelly Olova & Hannah Sutcliffe & Jacqueline K. Rainger & Andrea Leitch & Ruby T. Osborn & A, 2017. "cGAS surveillance of micronuclei links genome instability to innate immunity," Nature, Nature, vol. 548(7668), pages 461-465, August.
    4. Yuichiro Watanabe & Shinya Honda & Akimitsu Konishi & Satoko Arakawa & Michiko Murohashi & Hirofumi Yamaguchi & Satoru Torii & Minoru Tanabe & Shinji Tanaka & Eiji Warabi & Shigeomi Shimizu, 2016. "Autophagy controls centrosome number by degrading Cep63," Nature Communications, Nature, vol. 7(1), pages 1-12, December.
    5. Christopher J. Lord & Alan Ashworth, 2012. "The DNA damage response and cancer therapy," Nature, Nature, vol. 481(7381), pages 287-294, January.
    6. Caroline Park & Yousin Suh & Ana Maria Cuervo, 2015. "Regulated degradation of Chk1 by chaperone-mediated autophagy in response to DNA damage," Nature Communications, Nature, vol. 6(1), pages 1-14, November.
    7. Harith Rajagopalan & Christoph Lengauer, 2004. "Aneuploidy and cancer," Nature, Nature, vol. 432(7015), pages 338-341, November.
    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. Shengrui Feng & Sajid A. Marhon & Dustin J. Sokolowski & Alister D’Costa & Fraser Soares & Parinaz Mehdipour & Charles Ishak & Helen Loo Yau & Ilias Ettayebi & Parasvi S. Patel & Raymond Chen & Jiming, 2024. "Inhibiting EZH2 targets atypical teratoid rhabdoid tumor by triggering viral mimicry via both RNA and DNA sensing pathways," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    2. Zaili Luo & Dazhuan Xin & Yunfei Liao & Kalen Berry & Sean Ogurek & Feng Zhang & Liguo Zhang & Chuntao Zhao & Rohit Rao & Xinran Dong & Hao Li & Jianzhong Yu & Yifeng Lin & Guoying Huang & Lingli Xu &, 2023. "Loss of phosphatase CTDNEP1 potentiates aggressive medulloblastoma by triggering MYC amplification and genomic instability," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    3. Christopher P. Wardlaw & John H. J. Petrini, 2022. "ISG15 conjugation to proteins on nascent DNA mitigates DNA replication stress," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    4. Daipayan Banerjee & Kurt Langberg & Salar Abbas & Eric Odermatt & Praveen Yerramothu & Martin Volaric & Matthew A. Reidenbach & Kathy J. Krentz & C. Dustin Rubinstein & David L. Brautigan & Tarek Abba, 2021. "A non-canonical, interferon-independent signaling activity of cGAMP triggers DNA damage response signaling," Nature Communications, Nature, vol. 12(1), pages 1-24, December.
    5. Chun Zhou & Yun Wang & Yikun Huang & Yongpan An & Xian Fu & Daqian Yang & Yilin Wang & Jintao Zhang & Leslie A. Mitchell & Joel S. Bader & Yizhi Cai & Junbiao Dai & Jef D. Boeke & Zhiming Cai & Zhengw, 2024. "The de novo design and synthesis of yeast chromosome XIII facilitates investigations on aging," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    6. Kate M. MacDonald & Shirony Nicholson-Puthenveedu & Maha M. Tageldein & Sarika Khasnis & Cheryl H. Arrowsmith & Shane M. Harding, 2023. "Antecedent chromatin organization determines cGAS recruitment to ruptured micronuclei," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    7. Cuige Zhu & Mari Iwase & Ziqian Li & Faliang Wang & Annabel Quinet & Alessandro Vindigni & Jieya Shao, 2022. "Profilin-1 regulates DNA replication forks in a context-dependent fashion by interacting with SNF2H and BOD1L," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    8. Xiujie Liang & Hongbo Liu & Hailong Hu & Eunji Ha & Jianfu Zhou & Amin Abedini & Andrea Sanchez-Navarro & Konstantin A. Klötzer & Katalin Susztak, 2024. "TET2 germline variants promote kidney disease by impairing DNA repair and activating cytosolic nucleotide sensors," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    9. William Lee & Robert P St.Onge & Michael Proctor & Patrick Flaherty & Michael I Jordan & Adam P Arkin & Ronald W Davis & Corey Nislow & Guri Giaever, 2005. "Genome-Wide Requirements for Resistance to Functionally Distinct DNA-Damaging Agents," PLOS Genetics, Public Library of Science, vol. 1(2), pages 1-1, August.
    10. Ramona N. Moro & Uddipta Biswas & Suhas S. Kharat & Filip D. Duzanic & Prosun Das & Maria Stavrou & Maria C. Raso & Raimundo Freire & Arnab Ray Chaudhuri & Shyam K. Sharan & Lorenza Penengo, 2023. "Interferon restores replication fork stability and cell viability in BRCA-defective cells via ISG15," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    11. Ami G Sangster & Robert J Gooding & Andrew Garven & Hamid Ghaedi & David M Berman & Scott K Davey, 2022. "Mutually exclusive mutation profiles define functionally related genes in muscle invasive bladder cancer," PLOS ONE, Public Library of Science, vol. 17(1), pages 1-17, January.
    12. Tanaz Sharifnia & Mathias J. Wawer & Amy Goodale & Yenarae Lee & Mariya Kazachkova & Joshua M. Dempster & Sandrine Muller & Joan Levy & Daniel M. Freed & Josh Sommer & Jérémie Kalfon & Francisca Vazqu, 2023. "Mapping the landscape of genetic dependencies in chordoma," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    13. Ivo A. Hendriks & Sara C. Buch-Larsen & Evgeniia Prokhorova & Jonas D. Elsborg & Alexandra K.L.F.S. Rebak & Kang Zhu & Dragana Ahel & Claudia Lukas & Ivan Ahel & Michael L. Nielsen, 2021. "The regulatory landscape of the human HPF1- and ARH3-dependent ADP-ribosylome," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    14. Tomoko Yamamori Morita & Jie Yu & Yukie Kashima & Ryo Kamata & Gaku Yamamoto & Tatsunori Minamide & Chiaki Mashima & Miyuki Yoshiya & Yuta Sakae & Toyohiro Yamauchi & Yumi Hakozaki & Shun-ichiro Kagey, 2023. "CDC7 inhibition induces replication stress-mediated aneuploid cells with an inflammatory phenotype sensitizing tumors to immune checkpoint blockade," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    15. Lina Wang & Siru Li & Kai Wang & Na Wang & Qiaoling Liu & Zhen Sun & Li Wang & Lulu Wang & Quentin Liu & Chengli Song & Caigang Liu & Qingkai Yang, 2022. "DNA mechanical flexibility controls DNA potential to activate cGAS-mediated immune surveillance," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    16. Albert Stuart Reece & Gary Kenneth Hulse, 2022. "Cannabis- and Substance-Related Epidemiological Patterns of Chromosomal Congenital Anomalies in Europe: Geospatiotemporal and Causal Inferential Study," IJERPH, MDPI, vol. 19(18), pages 1-51, September.
    17. M. J. Gutbrod & B. Roche & J. I. Steinberg & A. A. Lakhani & K. Chang & A. J. Schorn & R. A. Martienssen, 2022. "Dicer promotes genome stability via the bromodomain transcriptional co-activator BRD4," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    18. Hyo Geun Choi & Jung Ho Park & Yeon Ju Choi & Yong Joon Suh, 2021. "Association of Family History with the Development of Breast Cancer: A Cohort Study of 129,374 Women in KoGES Data," IJERPH, MDPI, vol. 18(12), pages 1-9, June.
    19. Hanrui Zhang & Julian Kreis & Sven-Eric Schelhorn & Heike Dahmen & Thomas Grombacher & Michael Zühlsdorf & Frank T. Zenke & Yuanfang Guan, 2023. "Mapping combinatorial drug effects to DNA damage response kinase inhibitors," Nature Communications, Nature, vol. 14(1), pages 1-8, December.
    20. Viola Nähse & Camilla Raiborg & Kia Wee Tan & Sissel Mørk & Maria Lyngaas Torgersen & Eva Maria Wenzel & Mireia Nager & Veijo T. Salo & Terje Johansen & Elina Ikonen & Kay Oliver Schink & Harald Stenm, 2023. "ATPase activity of DFCP1 controls selective autophagy," Nature Communications, Nature, vol. 14(1), pages 1-15, 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:14:y:2023:i:1:d:10.1038_s41467-023-40952-0. 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.