bims-iorami Biomed News
on Ionising Radiation and Mitochondria
Issue of 2024‒03‒24
eight papers selected by
Chenxiao Yu, Soochow University
  1. mtDNA regulates cGAS-STING signaling pathway in adenomyosis.
  2. Mutant huntingtin protein induces MLH1 degradation, DNA hyperexcision, and cGAS-STING-dependent apoptosis.
  3. Targeting two radiation-induced immunosuppressive pathways to improve the efficacy of normofractionated radiation therapy in a preclinical colorectal cancer model.
  4. cGAS-STING pathway mediates activation of dendritic cell sensing of immunogenic tumors.
  5. TRIM28 facilitates type I interferon activation by targeting TBK1.
  6. Sensing of mitochondrial DNA by ZBP1 promotes RIPK3-mediated necroptosis and ferroptosis in response to diquat poisoning.
  7. Endogenous BAX and BAK form mosaic rings of variable size and composition on apoptotic mitochondria.
  8. STING activation reprograms the microenvironment to sensitize NF1-related malignant peripheral nerve sheath tumors for immunotherapy.
  1. Free Radic Biol Med. 2024 Mar 15. pii: S0891-5849(24)00137-0. [Epub ahead of print]216 80-88
    mtDNA regulates cGAS-STING signaling pathway in adenomyosis.
    Kun Wang, Yi Wen, Xianyun Fu, Shaobin Wei, Shidan Liu, Minmin Chen.
      In various hyperproliferative disorders, damaged mitochondria can release mitochondrial DNA (mtDNA) into the cytoplasm, activating the cGAS-STING signaling pathway and subsequent immune imbalances. Our previous research has demonstrated that hypoxia plays a role in the development of adenomyosis (AM) by inducing mitochondrial dysfunction. However, the precise involvement of the cGAS-STING signaling pathway and mtDNA in AM remains unclear. Therefore, this study aims to investigate the relationship between mtDNA secretion, changes in the cGAS-STING signaling pathway, and the abnormal cellular proliferation observed in AM. We found the cGAS, STING, TBK1, p-TBK1, IRF3, and p-IRF3 proteins levels were significantly elevated in the tissues of patients with AM compared to the control group. Additionally, there was an increase in the expression of the pro-inflammatory cytokines IL-6 and IFN-α in the AM tissues. Hypoxia-induced an increase in the proliferation and migration abilities of endometrial stromal cells (ESCs), accompanied by the activation of the cGAS-STING signaling pathway and elevated levels of IFN-α. Furthermore, hypoxia promoted the leakage of mtDNA into the cytoplasm in AM ESCs, and the deletion of mtDNA reduced the activation of the cGAS-STING pathway. Moreover, knockdown of the STING gene inhibited the expression of TBK1, p-TBK1, IRF3, and p-IRF3 and suppressed the secretion of the inflammatory cytokines IL-6 and IFN-α. Furthermore, the migration and invasion abilities of AM ESCs were significantly diminished after STING knockdown. These findings provide valuable insights into the role of mtDNA release and the cGAS-STING signaling pathway in the pathogenesis of AM.
    Keywords:  Adenomyosis; cGAS-STING signaling; mtDNA
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.03.012
  2. Proc Natl Acad Sci U S A. 2024 Mar 26. 121(13): e2313652121
    Mutant huntingtin protein induces MLH1 degradation, DNA hyperexcision, and cGAS-STING-dependent apoptosis.
    Xiao Sun, Lu Liu, Chao Wu, Xueying Li, Jinzhen Guo, Junqiu Zhang, Junhong Guan, Nan Wang, Liya Gu, X Willian Yang, Guo-Min Li.
      Huntington's disease (HD) is an inherited neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin (HTT) gene. The repeat-expanded HTT encodes a mutated HTT (mHTT), which is known to induce DNA double-strand breaks (DSBs), activation of the cGAS-STING pathway, and apoptosis in HD. However, the mechanism by which mHTT triggers these events is unknown. Here, we show that HTT interacts with both exonuclease 1 (Exo1) and MutLα (MLH1-PMS2), a negative regulator of Exo1. While the HTT-Exo1 interaction suppresses the Exo1-catalyzed DNA end resection during DSB repair, the HTT-MutLα interaction functions to stabilize MLH1. However, mHTT displays a significantly reduced interaction with Exo1 or MutLα, thereby losing the ability to regulate Exo1. Thus, cells expressing mHTT exhibit rapid MLH1 degradation and hyperactive DNA excision, which causes severe DNA damage and cytosolic DNA accumulation. This activates the cGAS-STING pathway to mediate apoptosis. Therefore, we have identified unique functions for both HTT and mHTT in modulating DNA repair and the cGAS-STING pathway-mediated apoptosis by interacting with MLH1. Our work elucidates the mechanism by which mHTT causes HD.
    Keywords:  Exo1; Huntington’s disease; MutLα; cGAS-STING; mHTT
    DOI:  https://doi.org/10.1073/pnas.2313652121
  3. Int J Radiat Biol. 2024 Mar 20. 1-10
    Targeting two radiation-induced immunosuppressive pathways to improve the efficacy of normofractionated radiation therapy in a preclinical colorectal cancer model.
    Jihane Boustani, Benoit Lecoester, Jérémy Baude, Charlène Latour, Emeric Limagne, Riad Ladjohoulou, Véronique Morgand, Lisa Froidurot, François Ghiringhelli, Gilles Truc, Olivier Adotévi, Céline Mirjolet.
      PURPOSE: We have previously demonstrated in a murine colorectal cancer model that normofractionated RT (normoRT: 18 × 2 Gy) induced MDSC infiltration and PD-L1 expression, while hypofractionated RT (hypoRT: 3 × 8 Gy) induced Treg. Here, we wanted to assess whether the association of normoRT with treatments that target two radiation-induced immunosuppressive pathways (MDSC and PD-L1) could improve tumor control.MATERIALS AND METHODS: Subcutaneous tumors were induced using colon tumor cells (CT26) in immunocompetent mice (BALB/c) and were treated with RT alone (18 × 2 Gy or 3 × 8 Gy), or concomitantly with 5-Fluorouracil (5FU) (10 mg/kg) to deplete MDSC, and/or anti-PD-L1 (10 mg/kg). We assessed the impact of these combinations on tumor growth and immune cells infiltration by flow cytometry. In addition, we performed tumor rechallenge experiments and IFN-γ ELISpots to study the long-term memory response.
    RESULTS: Even though tumor growth was significantly delayed in the RT + 5FU compared to 5FU and untreated groups (p < .05), there was no significant difference between RT + 5FU (CRT) and RT alone. The rate of MDSC increased significantly 1 week after the end of normoRT (8.09% ± 1.03%, p < .05) and decreased with the addition of 5FU (3.39% ± 0.69%, p < .05). PD-L1 expressing tumor cells were increased after treatment. Adding anti-PD-L1 significantly delayed tumor growth, achieved the highest complete response rate, and induced a long-lasting protective specific anti-tumor immunity.
    CONCLUSIONS: These results tend to demonstrate the interest of inhibiting two radiation-induced immunosuppressive mechanisms. In patients, the combination of normoRT with 5FU is already the standard of care in locally advanced rectal cancer. Adding an anti-PD-L1 to this treatment could show promising results.
    Keywords:  Radiation therapy; fractionation; immunosuppressive pathways; immunotherapy; treatment combination
    DOI:  https://doi.org/10.1080/09553002.2024.2331115
  4. Cell Mol Life Sci. 2024 Mar 21. 81(1): 149
    cGAS-STING pathway mediates activation of dendritic cell sensing of immunogenic tumors.
    Guohao Li, Xiangqian Zhao, Zuda Zheng, Hucheng Zhang, Yundi Wu, Yangkun Shen, Qi Chen.
      Type I interferons (IFN-I) play pivotal roles in tumor therapy for three decades, underscoring the critical importance of maintaining the integrity of the IFN-1 signaling pathway in radiotherapy, chemotherapy, targeted therapy, and immunotherapy. However, the specific mechanism by which IFN-I contributes to these therapies, particularly in terms of activating dendritic cells (DCs), remains unclear. Based on recent studies, aberrant DNA in the cytoplasm activates the cyclic GMP-AMP synthase (cGAS)- stimulator of interferon genes (STING) signaling pathway, which in turn produces IFN-I, which is essential for antiviral and anticancer immunity. Notably, STING can also enhance anticancer immunity by promoting autophagy, inflammation, and glycolysis in an IFN-I-independent manner. These research advancements contribute to our comprehension of the distinctions between IFN-I drugs and STING agonists in the context of oncology therapy and shed light on the challenges involved in developing STING agonist drugs. Thus, we aimed to summarize the novel mechanisms underlying cGAS-STING-IFN-I signal activation in DC-mediated antigen presentation and its role in the cancer immune cycle in this review.
    Keywords:  DC; Tumor immune cycle; Type I interferon; cGAS-STING pathway
    DOI:  https://doi.org/10.1007/s00018-024-05191-6
  5. Front Immunol. 2024 ;15 1279920
    TRIM28 facilitates type I interferon activation by targeting TBK1.
    Fang Hua, Tim Nass, Kislay Parvatiyar.
      Type I interferons play a fundamental role in innate host defense against viral infections by eliciting the induction of an antiviral gene program that serves to inhibit viral replication. Activation of type I interferon is regulated by the IRF3 transcription factor, which undergoes phosphorylation-dependent activation by the upstream kinase, TBK1, during viral infection. However, the mechanisms by which TBK1 achieves activation to support signaling to IRF3 remain incompletely understood. Here we identified the E3 ubiquitin ligase, tripartite motif containing 28 (TRIM28), as a positive regulator of type I interferon activation by facilitating TBK1 signaling. Genetic deletion of TRIM28 via CRISPR-Cas9 editing resulted in impaired type I interferon activation upon both RNA and DNA virus challenge, corresponding with increased susceptibility to virus infections in TRIM28 knockout cells. Mechanistically, TRIM28 interacted with TBK1 and mediated the assembly of K63-linked ubiquitin chains onto TBK1, a post-translational modification shown to augment TBK1 signal transmission events. TRIM28 knockout cells further displayed defective TBK1 phosphorylation and complex assembly with IRF3, resulting in impaired IRF3 phosphorylation. Altogether, our data demonstrate TBK1 to be a novel substrate for TRIM28 and identify TRIM28 as an essential regulatory factor in controlling innate antiviral immune responses.
    Keywords:  TBK1; TRIM28; pattern recognition receptor (PRR); tripartite motif containing 28; type I interferon (IFN)
    DOI:  https://doi.org/10.3389/fimmu.2024.1279920
  6. Cell Death Differ. 2024 Mar 16.
    Sensing of mitochondrial DNA by ZBP1 promotes RIPK3-mediated necroptosis and ferroptosis in response to diquat poisoning.
    Kunmei Lai, Junjie Wang, Siyi Lin, Zhimin Chen, Guo Lin, Keng Ye, Ying Yuan, Yujiao Lin, Chuan-Qi Zhong, Jianfeng Wu, Huabin Ma, Yanfang Xu.
      Diquat (DQ) poisoning is a severe medical condition associated with life-threatening implications and multiorgan dysfunction. Despite its clinical significance, the precise underlying mechanism remains inadequately understood. This study elucidates that DQ induces instability in the mitochondrial genome of endothelial cells, resulting in the accumulation of Z-form DNA. This process activates Z-DNA binding protein 1 (ZBP1), which then interacts with receptor-interacting protein kinase 3 (RIPK3), ultimately leading to RIPK3-dependent necroptotic and ferroptotic signaling cascades. Specific deletion of either Zbp1 or Ripk3 in endothelial cells simultaneously inhibits both necroptosis and ferroptosis. This dual inhibition significantly reduces organ damage and lowers mortality rate. Notably, our investigation reveals that RIPK3 has a dual role. It not only phosphorylates MLKL to induce necroptosis but also phosphorylates FSP1 to inhibit its enzymatic activity, promoting ferroptosis. The study further shows that deletion of mixed lineage kinase domain-like (Mlkl) and the augmentation of ferroptosis suppressor protein 1 (FSP1)-dependent non-canonical vitamin K cycling can provide partial protection against DQ-induced organ damage. Combining Mlkl deletion with vitamin K treatment demonstrates a heightened efficacy in ameliorating multiorgan damage and lethality induced by DQ. Taken together, this study identifies ZBP1 as a crucial sensor for DQ-induced mitochondrial Z-form DNA, initiating RIPK3-dependent necroptosis and ferroptosis. These findings suggest that targeting the ZBP1/RIPK3-dependent necroptotic and ferroptotic pathways could be a promising approach for drug interventions aimed at mitigating the adverse consequences of DQ poisoning.
    DOI:  https://doi.org/10.1038/s41418-024-01279-5
  7. Cell Death Differ. 2024 Mar 19.
    Endogenous BAX and BAK form mosaic rings of variable size and composition on apoptotic mitochondria.
    Sarah V Schweighofer, Daniel C Jans, Jan Keller-Findeisen, Anne Folmeg, Peter Ilgen, Mark Bates, Stefan Jakobs.
      One hallmark of apoptosis is the oligomerization of BAX and BAK to form a pore in the mitochondrial outer membrane, which mediates the release of pro-apoptotic intermembrane space proteins into the cytosol. Cells overexpressing BAX or BAK fusion proteins are a powerful model system to study the dynamics and localization of these proteins in cells. However, it is unclear whether overexpressed BAX and BAK form the same ultrastructural assemblies following the same spatiotemporal hierarchy as endogenously expressed proteins. Combining live- and fixed-cell STED super-resolution microscopy, we show that overexpression of BAK results in novel BAK structures, which are virtually absent in non-overexpressing apoptotic cells. We further demonstrate that in wild type cells, BAK is recruited to apoptotic pores before BAX. Both proteins together form unordered, mosaic rings on apoptotic mitochondria in immortalized cell culture models as well as in human primary cells. In BAX- or BAK- single-knockout cells, the remaining protein is able to form rings independently. The heterogeneous nature of these rings in both wild type as well as single-knockout cells corroborates the toroidal apoptotic pore model.
    DOI:  https://doi.org/10.1038/s41418-024-01273-x
  8. J Clin Invest. 2024 Mar 19. pii: e176748. [Epub ahead of print]
    STING activation reprograms the microenvironment to sensitize NF1-related malignant peripheral nerve sheath tumors for immunotherapy.
    Bandarigoda N Somatilaka, Laasya Madana, Ali Sadek, Zhiguo Chen, Sanjay Chandrasekaran, Renee M McKay, Lu Q Le.
      Neurofibromatosis Type 1 (NF1) is caused by mutations in the NF1 gene that encodes neurofibromin, a RAS GTPase-Activating Protein. Inactivating NF1 mutations cause hyperactivation of RAS-mediated signaling, resulting in development of multiple neoplasms, including Malignant Peripheral Nerve Sheath Tumors (MPNSTs). MPNSTs are an aggressive tumor and the main cause of mortality in NF1 patients. MPNSTs are difficult to resect and refractory to chemo- and radiotherapy, and no molecular therapies currently exist. Immune Checkpoint Blockade (ICB) is an approach to treat inoperable, undruggable cancers like MPNST, but successful outcomes require an immune cell-rich tumor microenvironment (TME). While MPNSTs are non-inflamed "cold" tumors, here, we turned MPNSTs into T cell-inflamed "hot" tumors by activating "stimulator of interferon genes" (STING) signaling. Mouse genetic and human xenograft MPNST models treated with STING agonist plus ICB exhibited growth delay via increased apoptotic cell death. This strategy offers a potential treatment regimen for MPNST.
    Keywords:  Cancer immunotherapy; Immunotherapy; Oncology; Therapeutics
    DOI:  https://doi.org/10.1172/JCI176748
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