Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
HO-1 impairs the efficacy of radiotherapy by redistributing cGAS and STING in tumors
Chuqing Zhang, … , Cheng Xu, Xiaoyu Liang
Chuqing Zhang, … , Cheng Xu, Xiaoyu Liang
Published December 2, 2024
Citation Information: J Clin Invest. 2024;134(23):e181044. https://doi.org/10.1172/JCI181044.
View: Text | PDF
Research Article Immunology Oncology Article has an altmetric score of 13

HO-1 impairs the efficacy of radiotherapy by redistributing cGAS and STING in tumors

  • Text
  • PDF
Abstract

Type I IFNs (IFN-Is) induced by radiotherapy (RT) are critical for its efficacy, while the mechanism by which tumor cells inhibit IFN-I production remains largely unsolved. By an unbiased CRISPR screen, we identified hemeoxygenase 1 (HO-1) as an RT-related regulator of IFN-I production. Mechanistically, the ER-anchored, full-length HO-1 disrupted stimulator of IFN genes (STING) polymerization and subsequent coat protein complex II–mediated (COPII-mediated) ER-Golgi transportation, leading to hampered activation of downstream signaling. This process was exacerbated by the upregulation of HO-1 expression under RT. Importantly, RT also induced HO-1 cleavage. Cleaved HO-1 underwent nuclear translocation, interacted with cyclic GMP-AMP synthase (cGAS), and inhibited its nuclear export upon irradiation, leading to suppressed 2′3′-cyclic GMP-AMP (cGAMP) production. Furthermore, we revealed that HO-1 inhibitors could enhance local and distant tumor control of RT in vivo. Clinically, higher HO-1 expression was associated with a poorer prognosis and earlier tumor relapse after RT in multiple types of patient tumors. Collectively, through comprehensive inhibition of the cGAS/STING pathway, HO-1 strongly inhibited RT-induced IFN-I production, and targeting HO-1 was shown to be a promising RT-sensitizing therapeutic strategy.

Authors

Chuqing Zhang, Zhenji Deng, Jiawei Wu, Cong Ding, Zhe Li, Zhimin Xu, Weipeng Chen, Kaibin Yang, Hanmiao Wei, Tingxiang He, Liufen Long, Jun Ma, Cheng Xu, Xiaoyu Liang

×

Figure 6

Cleaved HO-1 directly interacts with cGAS in the nucleus.

Options: View larger image (or click on image) Download as PowerPoint
Cleaved HO-1 directly interacts with cGAS in the nucleus.
(A and C) Cyto...
(A and C) Cytoplasmic and nuclear protein fractions were extracted for immunoblot analysis to determine the subcellular localization of cGAS in HK1 cells with the indicated cell lines and stimulation. (B and D) Subcellular distribution (cytoplasm and nucleus) of cGAS was determined with immunofluorescence staining of HK1 cells with the indicated cell lines and stimulation (scale bars: 10 μm). The percentages of cells (n = 200) in the nucleus, cytoplasm, or both the cytoplasm and nucleus were calculated (E) Confocal microscopy images of cGAS and HO-1 in HK1 cells before and after RT (scale bars: 10 μm). (F) The cytoplasmic and nuclear protein fractions of HK1 cells at the indicated RT time points were extracted for coimmunoprecipitation. (G and H) The interaction of HA-tagged full-length cGAS (aa 1–522), N-terminus of cGAS (aa 1–160), C-terminus of cGAS (aa 161–522), and Flag-tagged HO-1ΔTMS in HEK293T cells was analyzed by immunoprecipitation. (I) HMOX1-KO HK1 cells were stably transfected with cleaved HO-1 (HO-1ΔTMS). The interaction of endogenous cGAS and CRM1 in HK1 cells was analyzed by immunoprecipitation. All representative data from 1 experiment are shown (n = 3 biologically independent experiments).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Posted by 5 X users
On 1 Facebook pages
Referenced by 14 Bluesky users
5 readers on Mendeley
See more details