bims-nenemi Biomed News
on Neuroinflammation, neurodegeneration and mitochondria
Issue of 2023–09–10
twenty papers selected by
Marco Tigano, Thomas Jefferson University
  1. Lysosomes mediate the mitochondrial UPR via mTORC1-dependent ATF4 phosphorylation.
  2. eIF3d controls the persistent integrated stress response.
  3. Secretion of mitochondrial DNA via exosomes promotes inflammation in Behçet's syndrome.
  4. C17orf80 binds the mitochondrial genome to promote its replication.
  5. Damaged mitochondria recruit the effector NEMO to activate NF-κB signaling.
  6. Overexpression of the mitochondrial anti-viral signaling protein, MAVS, in cancers is associated with cell survival and inflammation.
  7. Antigen receptor stimulation induces purifying selection against pathogenic mitochondrial tRNA mutations.
  8. Activation of the integrated stress response by inhibitors of its kinases.
  9. PGAM5 exacerbates acute renal injury by initiating mitochondria-dependent apoptosis by facilitating mitochondrial cytochrome c release.
  10. Stat1 is an inducible transcriptional repressor of neural stem cells self-renewal program during neuroinflammation.
  11. Mammalian mitochondrial translation infidelity leads to oxidative stress-induced cell cycle arrest and cardiomyopathy.
  12. Viral sensing by epithelial cells involves PKR- and caspase-3-dependent generation of gasdermin E pores.
  13. Low-dose metronomic chemotherapy triggers oxidized mtDNA sensing inside tumor cells to potentiate CD8+T anti-tumor immunity.
  14. Molecular determinants of immunogenic cell death elicited by radiation therapy.
  15. Antagonism between viral infection and innate immunity at the single-cell level.
  16. TNFα induced by DNA-sensing in macrophage compromises retinal pigment epithelial (RPE) barrier function.
  17. Optogenetic engineering of STING signaling allows remote immunomodulation to enhance cancer immunotherapy.
  18. MAVS integrates glucose metabolism and RIG-I-like receptor signaling.
  19. Regulation with cell size ensures mitochondrial DNA homeostasis during cell growth.
  20. TRAP1 inhibits MARCH5-mediated MIC60 degradation to alleviate mitochondrial dysfunction and apoptosis of cardiomyocytes under diabetic conditions.
  1. Cell Discov. 2023 Sep 07. 9(1): 92
    Lysosomes mediate the mitochondrial UPR via mTORC1-dependent ATF4 phosphorylation.
    Terytty Yang Li, Qi Wang, Arwen W Gao, Xiaoxu Li, Yu Sun, Adrienne Mottis, Minho Shong, Johan Auwerx.
      Lysosomes are central platforms for not only the degradation of macromolecules but also the integration of multiple signaling pathways. However, whether and how lysosomes mediate the mitochondrial stress response (MSR) remain largely unknown. Here, we demonstrate that lysosomal acidification via the vacuolar H+-ATPase (v-ATPase) is essential for the transcriptional activation of the mitochondrial unfolded protein response (UPRmt). Mitochondrial stress stimulates v-ATPase-mediated lysosomal activation of the mechanistic target of rapamycin complex 1 (mTORC1), which then directly phosphorylates the MSR transcription factor, activating transcription factor 4 (ATF4). Disruption of mTORC1-dependent ATF4 phosphorylation blocks the UPRmt, but not other similar stress responses, such as the UPRER. Finally, ATF4 phosphorylation downstream of the v-ATPase/mTORC1 signaling is indispensable for sustaining mitochondrial redox homeostasis and protecting cells from ROS-associated cell death upon mitochondrial stress. Thus, v-ATPase/mTORC1-mediated ATF4 phosphorylation via lysosomes links mitochondrial stress to UPRmt activation and mitochondrial function resilience.
    DOI:  https://doi.org/10.1038/s41421-023-00589-1
  2. Mol Cell. 2023 Aug 30. pii: S1097-2765(23)00643-3. [Epub ahead of print]
    eIF3d controls the persistent integrated stress response.
    Shaoni Mukhopadhyay, Maria E Amodeo, Amy S Y Lee.
      Cells respond to intrinsic and extrinsic stresses by reducing global protein synthesis and activating gene programs necessary for survival. Here, we show that the integrated stress response (ISR) is driven by the non-canonical cap-binding protein eIF3d that acts as a critical effector to control core stress response orchestrators, the translation factor eIF2α and the transcription factor ATF4. We find that during persistent stress, eIF3d activates the translation of the kinase GCN2, inducing eIF2α phosphorylation and inhibiting general protein synthesis. In parallel, eIF3d upregulates the m6A demethylase ALKBH5 to drive 5' UTR-specific demethylation of stress response genes, including ATF4. Ultimately, this cascade converges on ATF4 expression by increasing mRNA engagement of translation machinery and enhancing ribosome bypass of upstream open reading frames (uORFs). Our results reveal that eIF3d acts in a life-or-death decision point during chronic stress and uncover a synergistic signaling mechanism in which translational cascades complement transcriptional amplification to control essential cellular processes.
    Keywords:  ATF4; GCN2; RNA methylation; eIF3d; integrated stress response; m(6)A; translation regulation
    DOI:  https://doi.org/10.1016/j.molcel.2023.08.008
  3. EMBO J. 2023 Sep 04. e112573
    Secretion of mitochondrial DNA via exosomes promotes inflammation in Behçet's syndrome.
    Hachiro Konaka, Yasuhiro Kato, Toru Hirano, Kohei Tsujimoto, JeongHoon Park, Taro Koba, Wataru Aoki, Yusei Matsuzaki, Masayasu Taki, Shohei Koyama, Eri Itotagawa, Tatsunori Jo, Takehiro Hirayama, Taro Kawai, Ken J Ishii, Mitsuyoshi Ueda, Shigehiro Yamaguchi, Shizuo Akira, Takayoshi Morita, Yuichi Maeda, Masayuki Nishide, Sumiyuki Nishida, Yoshihito Shima, Masashi Narazaki, Hyota Takamatsu, Atsushi Kumanogoh.
      Mitochondrial DNA (mtDNA) leakage into the cytoplasm can occur when cells are exposed to noxious stimuli. Specific sensors recognize cytoplasmic mtDNA to promote cytokine production. Cytoplasmic mtDNA can also be secreted extracellularly, leading to sterile inflammation. However, the mode of secretion of mtDNA out of cells upon noxious stimuli and its relevance to human disease remain unclear. Here, we show that pyroptotic cells secrete mtDNA encapsulated within exosomes. Activation of caspase-1 leads to mtDNA leakage from the mitochondria into the cytoplasm via gasdermin-D. Caspase-1 also induces intraluminal membrane vesicle formation, allowing for cellular mtDNA to be taken up and secreted as exosomes. Encapsulation of mtDNA within exosomes promotes a strong inflammatory response that is ameliorated upon exosome biosynthesis inhibition in vivo. We further show that monocytes derived from patients with Behçet's syndrome (BS), a chronic systemic inflammatory disorder, show enhanced caspase-1 activation, leading to exosome-mediated mtDNA secretion and similar inflammation pathology as seen in BS patients. Collectively, our findings support that mtDNA-containing exosomes promote inflammation, providing new insights into the propagation and exacerbation of inflammation in human inflammatory diseases.
    Keywords:  Behçet's syndrome; caspase-1; exosome; mitochondrial DNA; pyroptosis
    DOI:  https://doi.org/10.15252/embj.2022112573
  4. J Cell Biol. 2023 Oct 02. pii: e202302037. [Epub ahead of print]222(10):
    C17orf80 binds the mitochondrial genome to promote its replication.
    Hao Wu, Wenshuo Zhang, Fengli Xu, Kun Peng, Xiaoyu Liu, Wanqiu Ding, Qi Ma, Heping Cheng, Xianhua Wang.
      Serving as the power plant and signaling hub of a cell, mitochondria contain their own genome which encodes proteins essential for energy metabolism and forms DNA-protein assemblies called nucleoids. Mitochondrial DNA (mtDNA) exists in multiple copies within each cell ranging from hundreds to tens of thousands. Maintaining mtDNA homeostasis is vital for healthy cells, and its dysregulation causes multiple human diseases. However, the players involved in regulating mtDNA maintenance are largely unknown though the core components of its replication machinery have been characterized. Here, we identify C17orf80, a functionally uncharacterized protein, as a critical player in maintaining mtDNA homeostasis. C17orf80 primarily localizes to mitochondrial nucleoid foci and exhibits robust double-stranded DNA binding activity throughout the mitochondrial genome, thus constituting a bona fide new mitochondrial nucleoid protein. It controls mtDNA levels by promoting mtDNA replication and plays important roles in mitochondrial metabolism and cell proliferation. Our findings provide a potential target for therapeutics of human diseases associated with defective mtDNA control.
    DOI:  https://doi.org/10.1083/jcb.202302037
  5. Mol Cell. 2023 Sep 07. pii: S1097-2765(23)00641-X. [Epub ahead of print]83(17): 3188-3204.e7
    Damaged mitochondria recruit the effector NEMO to activate NF-κB signaling.
    Olivia Harding, Elisabeth Holzer, Julia F Riley, Sascha Martens, Erika L F Holzbaur.
      Failure to clear damaged mitochondria via mitophagy disrupts physiological function and may initiate damage signaling via inflammatory cascades, although how these pathways intersect remains unclear. We discovered that nuclear factor kappa B (NF-κB) essential regulator NF-κB effector molecule (NEMO) is recruited to damaged mitochondria in a Parkin-dependent manner in a time course similar to recruitment of the structurally related mitophagy adaptor, optineurin (OPTN). Upon recruitment, NEMO partitions into phase-separated condensates distinct from OPTN but colocalizing with p62/SQSTM1. NEMO recruitment, in turn, recruits the active catalytic inhibitor of kappa B kinase (IKK) component phospho-IKKβ, initiating NF-κB signaling and the upregulation of inflammatory cytokines. Consistent with a potential neuroinflammatory role, NEMO is recruited to mitochondria in primary astrocytes upon oxidative stress. These findings suggest that damaged, ubiquitinated mitochondria serve as an intracellular platform to initiate innate immune signaling, promoting the formation of activated IKK complexes sufficient to activate NF-κB signaling. We propose that mitophagy and NF-κB signaling are initiated as parallel pathways in response to mitochondrial stress.
    Keywords:  ALS; NEMO; NF-κB; NF-κB effector molecule; Parkin; Parkinson’s disease; SQSTM1/p62; amyotrophic lateral sclerosis; cell stress; innate immunity; mitophagy; neurodegeneration; neuroinflammation; optineurin nuclear factor kappa B; phase separation; ubiquitin
    DOI:  https://doi.org/10.1016/j.molcel.2023.08.005
  6. Mol Ther Nucleic Acids. 2023 Sep 12. 33 713-732
    Overexpression of the mitochondrial anti-viral signaling protein, MAVS, in cancers is associated with cell survival and inflammation.
    Sweta Trishna, Avia Lavon, Anna Shteinfer-Kuzmine, Avis Dafa-Berger, Varda Shoshan-Barmatz.
      Mitochondrial anti-viral signaling protein (MAVS) plays an important role in host defense against viral infection via coordinating the activation of NF-κB and interferon regulatory factors. The mitochondrial-bound form of MAVS is essential for its anti-viral innate immunity. Recently, tumor cells were proposed to mimic a viral infection by activating RNA-sensing pattern recognition receptors. Here, we demonstrate that MAVS is overexpressed in a panel of viral non-infected cancer cell lines and patient-derived tumors, including lung, liver, bladder, and cervical cancers, and we studied its role in cancer. Silencing MAVS expression reduced cell proliferation and the expression and nuclear translocation of proteins associated with transcriptional regulation, inflammation, and immunity. MAVS depletion reduced expression of the inflammasome components and inhibited its activation/assembly. Moreover, MAVS directly interacts with the mitochondrial protein VDAC1, decreasing its conductance, and we identified the VDAC1 binding site in MAVS. Our findings suggest that MAVS depletion, by reducing cancer cell proliferation and inflammation, represents a new target for cancer therapy.
    Keywords:  MAVS; MT: Non-coding RNAs; VISA; cancer; cell proliferation; inflammation; mitochondria; siRNA
    DOI:  https://doi.org/10.1016/j.omtn.2023.07.008
  7. JCI Insight. 2023 Sep 08. pii: e167656. [Epub ahead of print]8(17):
    Antigen receptor stimulation induces purifying selection against pathogenic mitochondrial tRNA mutations.
    Jingdian Zhang, Camilla Koolmeister, Jinming Han, Roberta Filograna, Leo Hanke, Monika Àdori, Daniel J Sheward, Sina Teifel, Shreekara Gopalakrishna, Qiuya Shao, Yong Liu, Keying Zhu, Robert A Harris, Gerald McInerney, Ben Murrell, Mike Aoun, Liselotte Bäckdahl, Rikard Holmdahl, Marcin Pekalski, Anna Wedell, Martin Engvall, Anna Wredenberg, Gunilla B Karlsson Hedestam, Xaquin Castro Dopico, Joanna Rorbach.
      Pathogenic mutations in mitochondrial (mt) tRNA genes that compromise oxidative phosphorylation (OXPHOS) exhibit heteroplasmy and cause a range of multisyndromic conditions. Although mitochondrial disease patients are known to suffer from abnormal immune responses, how heteroplasmic mtDNA mutations affect the immune system at the molecular level is largely unknown. Here, in mice carrying pathogenic C5024T in mt-tRNAAla and in patients with mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes (MELAS) syndrome carrying A3243G in mt-tRNALeu, we found memory T and B cells to have lower pathogenic mtDNA mutation burdens than their antigen-inexperienced naive counterparts, including after vaccination. Pathogenic burden reduction was less pronounced in myeloid compared with lymphoid lineages, despite C5024T compromising macrophage OXPHOS capacity. Rapid dilution of the C5024T mutation in T and B cell cultures could be induced by antigen receptor-triggered proliferation and was accelerated by metabolic stress conditions. Furthermore, we found C5024T to dysregulate CD8+ T cell metabolic remodeling and IFN-γ production after activation. Together, our data illustrate that the generation of memory lymphocytes shapes the mtDNA landscape, wherein pathogenic variants dysregulate the immune response.
    Keywords:  Adaptive immunity; Immunology; Metabolism; Mitochondria
    DOI:  https://doi.org/10.1172/jci.insight.167656
  8. Nat Commun. 2023 Sep 08. 14(1): 5535
    Activation of the integrated stress response by inhibitors of its kinases.
    Maria Szaruga, Dino A Janssen, Claudia de Miguel, George Hodgson, Agnieszka Fatalska, Aleksandra P Pitera, Antonina Andreeva, Anne Bertolotti.
      Phosphorylation of the translation initiation factor eIF2α to initiate the integrated stress response (ISR) is a vital signalling event. Protein kinases activating the ISR, including PERK and GCN2, have attracted considerable attention for drug development. Here we find that the widely used ATP-competitive inhibitors of PERK, GSK2656157, GSK2606414 and AMG44, inhibit PERK in the nanomolar range, but surprisingly activate the ISR via GCN2 at micromolar concentrations. Similarly, a PKR inhibitor, C16, also activates GCN2. Conversely, GCN2 inhibitor A92 silences its target but induces the ISR via PERK. These findings are pivotal for understanding ISR biology and its therapeutic manipulations because most preclinical studies used these inhibitors at micromolar concentrations. Reconstitution of ISR activation with recombinant proteins demonstrates that PERK and PKR inhibitors directly activate dimeric GCN2, following a Gaussian activation-inhibition curve, with activation driven by allosterically increasing GCN2 affinity for ATP. The tyrosine kinase inhibitors Neratinib and Dovitinib also activate GCN2 by increasing affinity of GCN2 for ATP. Thus, the mechanism uncovered here might be broadly relevant to ATP-competitive inhibitors and perhaps to other kinases.
    DOI:  https://doi.org/10.1038/s41467-023-40823-8
  9. Acta Pharmacol Sin. 2023 Sep 08.
    PGAM5 exacerbates acute renal injury by initiating mitochondria-dependent apoptosis by facilitating mitochondrial cytochrome c release.
    Jing-Yao Li, Xi-Ang Sun, Xin Wang, Ning-Hao Yang, Hong-Yan Xie, Heng-Jiang Guo, Li Lu, Xin Xie, Li Zhou, Jun Liu, Wei Zhang, Li-Min Lu.
      Acute kidney injury (AKI) is a worldwide public health problem characterized by the massive loss of tubular cells. However, the precise mechanism for initiating tubular cell death has not been fully elucidated. Here, we reported that phosphoglycerate mutase 5 (PGAM5) was upregulated in renal tubular epithelial cells during ischaemia/reperfusion or cisplatin-induced AKI in mice. PGAM5 knockout significantly alleviated the activation of the mitochondria-dependent apoptosis pathway and tubular apoptosis. Apoptosis inhibitors alleviated the activation of the mitochondria-dependent apoptosis pathway. Mechanistically, as a protein phosphatase, PGAM5 could dephosphorylate Bax and facilitate Bax translocation to the mitochondrial membrane. The translocation of Bax to mitochondria increased membrane permeability, decreased mitochondrial membrane potential and facilitated the release of mitochondrial cytochrome c (Cyt c) into the cytoplasm. Knockdown of Bax attenuated PGAM5 overexpression-induced Cyt c release and tubular cell apoptosis. Our results demonstrated that the increase in PGAM5-mediated Bax dephosphorylation and mitochondrial translocation was implicated in the development of AKI by initiating mitochondrial Cyt c release and activating the mitochondria-dependent apoptosis pathway. Targeting this axis might be beneficial for alleviating AKI.
    Keywords:  Bax; Cyt c; PGAM5; acute kidney injury; apoptosis; ischaemia/reperfusion injury
    DOI:  https://doi.org/10.1038/s41401-023-01151-1
  10. Front Cell Neurosci. 2023 ;17 1156802
    Stat1 is an inducible transcriptional repressor of neural stem cells self-renewal program during neuroinflammation.
    Jaime Imitola, Ethan W Hollingsworth, Fumihiro Watanabe, Marta Olah, Wassim Elyaman, Sarah Starossom, Pia Kivisäkk, Samia J Khoury.
      A central issue in regenerative medicine is understanding the mechanisms that regulate the self-renewal of endogenous stem cells in response to injury and disease. Interferons increase hematopoietic stem cells during infection by activating STAT1, but the mechanisms by which STAT1 regulates intrinsic programs in neural stem cells (NSCs) during neuroinflammation is less known. Here we explored the role of STAT1 on NSC self-renewal. We show that overexpressing Stat1 in NSCs derived from the subventricular zone (SVZ) decreases NSC self-renewal capacity while Stat1 deletion increases NSC self-renewal, neurogenesis, and oligodendrogenesis in isolated NSCs. Importantly, we find upregulation of STAT1 in NSCs in a mouse model of multiple sclerosis (MS) and an increase in pathological T cells expressing IFN-γ rather than interleukin 17 (IL-17) in the cerebrospinal fluid of affected mice. We find IFN-γ is superior to IL-17 in reducing proliferation and precipitating an abnormal NSC phenotype featuring increased STAT1 phosphorylation and Stat1 and p16ink4a gene expression. Notably, Stat1-/- NSCs were resistant to the effect of IFN-γ. Lastly, we identified a Stat1-dependent gene expression profile associated with an increase in the Sox9 transcription factor, a regulator of self-renewal. Stat1 binds and transcriptionally represses Sox9 in a transcriptional luciferase assay. We conclude that Stat1 serves as an inducible checkpoint for NSC self-renewal that is upregulated during chronic brain inflammation leading to decreased self-renewal. As such, Stat1 may be a potential target to modulate for next generation therapies to prevent progression and loss of repair function in NSCs/neural progenitors in MS.
    Keywords:  STAT1; Sox9; experimental autoimmune encephalomyelitis; interferons; multiple sclerosis; neural stem cells; subventricular zone
    DOI:  https://doi.org/10.3389/fncel.2023.1156802
  11. Proc Natl Acad Sci U S A. 2023 Sep 12. 120(37): e2309714120
    Mammalian mitochondrial translation infidelity leads to oxidative stress-induced cell cycle arrest and cardiomyopathy.
    Wen-Qiang Zheng, Jian-Hui Zhang, Zi-Han Li, Xiuxiu Liu, Yong Zhang, Shuo Huang, Jinsong Li, Bin Zhou, Gilbert Eriani, En-Duo Wang, Xiao-Long Zhou.
      Proofreading (editing) of mischarged tRNAs by cytoplasmic aminoacyl-tRNA synthetases (aaRSs), whose impairment causes neurodegeneration and cardiac diseases, is of high significance for protein homeostasis. However, whether mitochondrial translation needs fidelity and the significance of editing by mitochondrial aaRSs have been unclear. Here, we show that mammalian cells critically depended on the editing of mitochondrial threonyl-tRNA synthetase (mtThrRS, encoded by Tars2), disruption of which accumulated Ser-tRNAThr and generated a large abundance of Thr-to-Ser misincorporated peptides in vivo. Such infidelity impaired mitochondrial translation and oxidative phosphorylation, causing oxidative stress and cell cycle arrest in the G0/G1 phase. Notably, reactive oxygen species (ROS) scavenging by N-acetylcysteine attenuated this abnormal cell proliferation. A mouse model of heart-specific defective mtThrRS editing was established. Increased ROS levels, blocked cardiomyocyte proliferation, contractile dysfunction, dilated cardiomyopathy, and cardiac fibrosis were observed. Our results elucidate that mitochondria critically require a high level of translational accuracy at Thr codons and highlight the cellular dysfunctions and imbalance in tissue homeostasis caused by mitochondrial mistranslation.
    Keywords:  aminoacyl-tRNA synthetase; cardiomyopathy; editing; mitochondria; tRNA
    DOI:  https://doi.org/10.1073/pnas.2309714120
  12. iScience. 2023 Sep 15. 26(9): 107698
    Viral sensing by epithelial cells involves PKR- and caspase-3-dependent generation of gasdermin E pores.
    Coralie Guy, Marcin Baran, Pau Ribó-Molina, Bernadette G van den Hoogen, Andrew G Bowie.
      Viral sensing in myeloid cells involves inflammasome activation leading to gasdermin pore formation, cytokine release, and cell death. However, less is known about viral sensing in barrier epithelial cells, which are critical to the innate immune response to RNA viruses. Here, we show that poly(I:C), a mimic of viral dsRNA, is sensed by NLRP1 in human bronchial epithelial cells, leading to inflammasome-dependent gasdermin D (GSDMD) pore formation via caspase-1. DsRNA also stimulated a parallel sensing pathway via PKR which activated caspase-3 to cleave gasdermin E (GSDME) to form active pores. Influenza A virus (IAV) infection of cells caused GSDME activation, cytokine release, and cell death, in a PKR-dependent but NLRP1-independent manner, involving caspase-8 and caspase-3. Suppression of GSDMD and GSDME expression increased IAV replication. These data clarify mechanisms of gasdermin cleavage in response to viral sensing and reveal that gasdermin pore formation is intrinsically antiviral in human epithelial cells.
    Keywords:  Immunology; Virology
    DOI:  https://doi.org/10.1016/j.isci.2023.107698
  13. Cancer Lett. 2023 Sep 01. pii: S0304-3835(23)00321-X. [Epub ahead of print]573 216370
    Low-dose metronomic chemotherapy triggers oxidized mtDNA sensing inside tumor cells to potentiate CD8+T anti-tumor immunity.
    Wen Qiao, Cegui Hu, Jiayi Ma, Xinrui Dong, Sumiya Dalangood, Hanjun Li, Chenwei Yuan, Binbin Lu, Wei-Qiang Gao, Zhenke Wen, Wenjin Yin, Jun Gui.
      Low-dose metronomic (LDM) chemotherapy, the frequent and continuous use of low doses of conventional chemotherapeutics, is emerging as a promising form of chemotherapy utilization. LDM chemotherapy exerts immunomodulatory effects. However, the underlying mechanism is not fully understood. Here we found that suppressing tumor growth by LDM chemotherapy was dependent on the activation of CD8+T cells. LDM chemotherapy potentiated the cytotoxic function of CD8+T cells by stimulating cancer-cell autonomous type I interferon (IFN) induction. Mechanistically, LDM chemotherapy evoked mitochondrial dysfunction and increased reactive oxygen species (ROS) production. ROS triggered the oxidation of cytosolic mtDNA, which was sensed by cGAS-STING, consequently inducing type I IFN production in the cancer cells. Moreover, the cGAS-STING-IFN axis increased PD-L1 expression and predicted favorable clinical responses to chemoimmunotherapy. Antioxidant N-acetylcysteine inhibited oxidized mtDNA-induced type I IFN production and attenuated the efficacy of combination therapy with LDM chemotherapy and PD-L1 blockade. This study elucidates the critical role of intratumoral oxidized mtDNA sensing in LDM chemotherapy-mediated activation of CD8+T cell immune response. These findings may provide new insights for designing combinatorial immunotherapy for cancer patients.
    Keywords:  Chemoimmunotherapy; Cytotoxic T lymphocytes; Low-dose metronomic chemotherapy; Oxidized mtDNA; Type I interferon; cGAS/STING
    DOI:  https://doi.org/10.1016/j.canlet.2023.216370
  14. Immunol Rev. 2023 Sep 07.
    Molecular determinants of immunogenic cell death elicited by radiation therapy.
    Claudia Galassi, Vanessa Klapp, Takahiro Yamazaki, Lorenzo Galluzzi.
      Cancer cells undergoing immunogenic cell death (ICD) can initiate adaptive immune responses against dead cell-associated antigens, provided that (1) said antigens are not perfectly covered by central tolerance (antigenicity), (2) cell death occurs along with the emission of immunostimulatory cytokines and damage-associated molecular patterns (DAMPs) that actively engage immune effector mechanisms (adjuvanticity), and (3) the microenvironment of dying cells is permissive for the initiation of adaptive immunity. Finally, ICD-driven immune responses can only operate and exert cytotoxic effector functions if the microenvironment of target cancer cells enables immune cell infiltration and activity. Multiple forms of radiation, including non-ionizing (ultraviolet) and ionizing radiation, elicit bona fide ICD as they increase both the antigenicity and adjuvanticity of dying cancer cells. Here, we review the molecular determinants of ICD as elicited by radiation as we critically discuss strategies to reinforce the immunogenicity of cancer cells succumbing to clinically available radiation strategies.
    Keywords:  ATP; HMGB1; PD-L1; calreticulin; immune checkpoint inhibitors; type I IFN
    DOI:  https://doi.org/10.1111/imr.13271
  15. PLoS Pathog. 2023 Sep 05. 19(9): e1011597
    Antagonism between viral infection and innate immunity at the single-cell level.
    Frederic Grabowski, Marek Kochańczyk, Zbigniew Korwek, Maciej Czerkies, Wiktor Prus, Tomasz Lipniacki.
      When infected with a virus, cells may secrete interferons (IFNs) that prompt nearby cells to prepare for upcoming infection. Reciprocally, viral proteins often interfere with IFN synthesis and IFN-induced signaling. We modeled the crosstalk between the propagating virus and the innate immune response using an agent-based stochastic approach. By analyzing immunofluorescence microscopy images we observed that the mutual antagonism between the respiratory syncytial virus (RSV) and infected A549 cells leads to dichotomous responses at the single-cell level and complex spatial patterns of cell signaling states. Our analysis indicates that RSV blocks innate responses at three levels: by inhibition of IRF3 activation, inhibition of IFN synthesis, and inhibition of STAT1/2 activation. In turn, proteins coded by IFN-stimulated (STAT1/2-activated) genes inhibit the synthesis of viral RNA and viral proteins. The striking consequence of these inhibitions is a lack of coincidence of viral proteins and IFN expression within single cells. The model enables investigation of the impact of immunostimulatory defective viral particles and signaling network perturbations that could potentially facilitate containment or clearance of the viral infection.
    DOI:  https://doi.org/10.1371/journal.ppat.1011597
  16. Sci Rep. 2023 Sep 02. 13(1): 14451
    TNFα induced by DNA-sensing in macrophage compromises retinal pigment epithelial (RPE) barrier function.
    Michael Twarog, Joshua Schustak, YongYao Xu, Matthew Coble, Katie Dolan, Robert Esterberg, Qian Huang, Magali Saint-Geniez, Yi Bao.
      Increasing evidence suggests that chronic inflammation plays an important role in the pathogenesis of age-related macular degeneration (AMD); however, the precise pathogenic stressors and sensors, and their impact on disease progression remain unclear. Several studies have demonstrated that type I interferon (IFN) response is activated in the retinal pigment epithelium (RPE) of AMD patients. Previously, we demonstrated that human RPE cells can initiate RNA-mediated type I IFN responses through RIG-I, yet are unable to directly sense and respond to DNA. In this study, we utilized a co-culture system combining primary human macrophage and iPS-derived RPE to study how each cell type responds to nucleic acids challenges and their effect on RPE barrier function in a homotypic and heterotypic manner. We find that DNA-induced macrophage activation induces an IFN response in the RPE, and compromises RPE barrier function via tight-junction remodeling. Investigation of the secreted cytokines responsible for RPE dysfunction following DNA-induced macrophages activation indicates that neutralization of macrophage-secreted TNFα, but not IFNβ, is sufficient to rescue RPE morphology and barrier function. Our data reveals a novel mechanism of intercellular communication by which DNA induces RPE dysfunction via macrophage-secreted TNFa, highlighting the complexity and potential pathological relevance of RPE and macrophage interactions.
    DOI:  https://doi.org/10.1038/s41598-023-41610-7
  17. Nat Commun. 2023 Sep 06. 14(1): 5461
    Optogenetic engineering of STING signaling allows remote immunomodulation to enhance cancer immunotherapy.
    Yaling Dou, Rui Chen, Siyao Liu, Yi-Tsang Lee, Ji Jing, Xiaoxuan Liu, Yuepeng Ke, Rui Wang, Yubin Zhou, Yun Huang.
      The cGAS-STING signaling pathway has emerged as a promising target for immunotherapy development. Here, we introduce a light-sensitive optogenetic device for control of the cGAS/STING signaling to conditionally modulate innate immunity, called 'light-inducible SMOC-like repeats' (LiSmore). We demonstrate that photo-activated LiSmore boosts dendritic cell (DC) maturation and antigen presentation with high spatiotemporal precision. This non-invasive approach photo-sensitizes cytotoxic T lymphocytes to engage tumor antigens, leading to a sustained antitumor immune response. When combined with an immune checkpoint blocker (ICB), LiSmore improves antitumor efficacy in an immunosuppressive lung cancer model that is otherwise unresponsive to conventional ICB treatment. Additionally, LiSmore exhibits an abscopal effect by effectively suppressing tumor growth in a distal site in a bilateral mouse model of melanoma. Collectively, our findings establish the potential of targeted optogenetic activation of the STING signaling pathway for remote immunomodulation in mice.
    DOI:  https://doi.org/10.1038/s41467-023-41164-2
  18. Nat Commun. 2023 Sep 02. 14(1): 5343
    MAVS integrates glucose metabolism and RIG-I-like receptor signaling.
    Qiao-Qiao He, Yu Huang, Longyu Nie, Sheng Ren, Gang Xu, Feiyan Deng, Zhikui Cheng, Qi Zuo, Lin Zhang, Huanhuan Cai, Qiming Wang, Fubing Wang, Hong Ren, Huan Yan, Ke Xu, Li Zhou, Mengji Lu, Zhibing Lu, Ying Zhu, Shi Liu.
      MAVS is an adapter protein involved in RIG-I-like receptor (RLR) signaling in mitochondria, peroxisomes, and mitochondria-associated ER membranes (MAMs). However, the role of MAVS in glucose metabolism and RLR signaling cross-regulation and how these signaling pathways are coordinated among these organelles have not been defined. This study reports that RLR action drives a switch from glycolysis to the pentose phosphate pathway (PPP) and the hexosamine biosynthesis pathway (HBP) through MAVS. We show that peroxisomal MAVS is responsible for glucose flux shift into PPP and type III interferon (IFN) expression, whereas MAMs-located MAVS is responsible for glucose flux shift into HBP and type I IFN expression. Mechanistically, peroxisomal MAVS interacts with G6PD and the MAVS signalosome forms at peroxisomes by recruiting TNF receptor-associated factor 6 (TRAF6) and interferon regulatory factor 1 (IRF1). By contrast, MAMs-located MAVS interact with glutamine-fructose-6-phosphate transaminase, and the MAVS signalosome forms at MAMs by recruiting TRAF6 and TRAF2. Our findings suggest that MAVS mediates the interaction of RLR signaling and glucose metabolism.
    DOI:  https://doi.org/10.1038/s41467-023-41028-9
  19. Nat Struct Mol Biol. 2023 Sep 07.
    Regulation with cell size ensures mitochondrial DNA homeostasis during cell growth.
    Anika Seel, Francesco Padovani, Moritz Mayer, Alissa Finster, Daniela Bureik, Felix Thoma, Christof Osman, Till Klecker, Kurt M Schmoller.
      To maintain stable DNA concentrations, proliferating cells need to coordinate DNA replication with cell growth. For nuclear DNA, eukaryotic cells achieve this by coupling DNA replication to cell-cycle progression, ensuring that DNA is doubled exactly once per cell cycle. By contrast, mitochondrial DNA replication is typically not strictly coupled to the cell cycle, leaving the open question of how cells maintain the correct amount of mitochondrial DNA during cell growth. Here, we show that in budding yeast, mitochondrial DNA copy number increases with cell volume, both in asynchronously cycling populations and during G1 arrest. Our findings suggest that cell-volume-dependent mitochondrial DNA maintenance is achieved through nuclear-encoded limiting factors, including the mitochondrial DNA polymerase Mip1 and the packaging factor Abf2, whose amount increases in proportion to cell volume. By directly linking mitochondrial DNA maintenance to nuclear protein synthesis and thus cell growth, constant mitochondrial DNA concentrations can be robustly maintained without a need for cell-cycle-dependent regulation.
    DOI:  https://doi.org/10.1038/s41594-023-01091-8
  20. Cell Death Differ. 2023 Sep 07.
    TRAP1 inhibits MARCH5-mediated MIC60 degradation to alleviate mitochondrial dysfunction and apoptosis of cardiomyocytes under diabetic conditions.
    Lingxiao Zhang, Yuanyuan Luo, Linyan Lv, Siyong Chen, Guihua Liu, Tongfeng Zhao.
      Mitochondrial dysfunction and cell death play important roles in diabetic cardiomyopathy, but the underlying mechanisms remain unclear. Here, we report that mitochondrial dysfunction and cell apoptosis are prominent features of primary cardiomyocytes after exposure to high glucose/palmitate conditions. The protein level of MIC60, a core component of mitochondrial cristae, is decreased via ubiquitination and degradation under these conditions. Exogenous expression of MIC60 alleviates cristae disruption, mitochondrial dysfunction and apoptosis. Moreover, we identified MARCH5 as an E3 ubiquitin ligase that specifically targets MIC60 in this process. Indeed, MARCH5 mediates K48-linked ubiquitination of MIC60 at Lys285 to promote its degradation. Mutation of the ubiquitination site in MIC60 or the MIC60-interacting motifs in MARCH5 abrogates MARCH5-mediated MIC60 ubiquitination and degradation. Silencing MARCH5 significantly alleviates high glucose/palmitate-induced mitochondrial dysfunction and apoptosis in primary cardiomyocytes. In addition to E3 ubiquitin ligases, molecular chaperones also play important roles in protein stability. We previously reported that the mitochondrial chaperone TRAP1 inhibits the ubiquitination of MIC60, but the detailed mechanism is unknown. Here, we find that TRAP1 performs this function by competing with MARCH5 for binding to MIC60. Our findings provide new insights into the mechanism underlying mitochondrial dysfunction in cardiomyocytes in diabetic cardiomyopathy. MARCH5 promotes ubiquitination of MIC60 to induce MIC60 degradation, mitochondrial dysfunction and apoptosis in cardiomyocytes under diabetic conditions. TRAP1 inhibits MARCH5-mediated ubiquitination by competitively interacting with MIC60.
    DOI:  https://doi.org/10.1038/s41418-023-01218-w
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