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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.
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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

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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

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Figure 5

Cleaved HO-1 inhibits the nuclear export of cGAS.

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Cleaved HO-1 inhibits the nuclear export of cGAS.
(A–E) HMOX1-KO HK1 cel...
(A–E) HMOX1-KO HK1 cells were stably transfected with cleaved HO-1 (HO-1ΔTMS), exclusively nucleus-located cleaved HO-1 (NLS-HO-1ΔTMS), or exclusively cytoplasm-located cleaved HO-1 (NES-HO-1ΔTMS) individually. (A and B) ELISA of cGAMP (A) or IFN-β (B) production before and after RT. (C) The interaction of Flag-tagged HO-1 mutants and HA-tagged cGAS in HEK293T cells was analyzed by immunoprecipitation under RT. WCL, whole-cell lysate. (D, F, and H) Subcellular distribution (cytoplasm and nucleus) of cGAS was determined by immunofluorescence staining of HK1 cells with the indicated mutants or RT stimulation (scale bars: 10 μm). The percentages of cells (n = 200) in the nucleus, cytoplasm, or both the cytoplasm and nucleus were calculated. (E and G) The cytoplasmic and nuclear protein fractions were extracted for immunoblot analysis to determine the subcellular localization of cGAS in HK1 cells with the indicated mutants or RT stimulation. (I and J) ELISA of cGAMP (I) or IFN-β (J) production before and after RT (related to Figure 5H). Data are shown as the mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 1-way ANOVA (A and B) and unpaired, 2-tailed Student’s t test (I and J). All representative data from 1 experiment are shown (n = 3 biologically independent experiments). N, predominantly in the nucleus; C, predominately in the cytoplasm; C+N, evenly distributed in the nucleus and cytoplasm.

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

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