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1. Trpv6 channel targeting using monoclonal antibody induces prostate cancer cell apoptosis and tumor regression

Author

Aurélien Haustrate, Clément Cordier, George Shapovalov, Adriana Mihalache, Emilie Desruelles, Benjamin Soret, Nadège Charlène Essonghé, Corentin Spriet, Maya Yassine, Alexandre Barras, Johanna Marines, Lindsay B. Alcaraz, Sabine Szunerits, Gautier Robin, Pierre Gosset, Natalia Prevarskaya, and V’yacheslav Lehen’kyi

Subjects
Cytology, QH573-671
Abstract

Abstract TRPV6 calcium channel is a prospective target in prostate cancer (PCa) since it is not expressed in healthy prostate while its expression increases during cancer progression. Despite the role of TRPV6 in PCa cell survival and apoptotic resistance has been already established, no reliable tool to target TRPV6 channel in vivo and thus to reduce tumor burden is known to date. Here we report the generation of mouse monoclonal antibody mAb82 raised against extracellular epitope of the pore region of the channel. mAb82 inhibited TRPV6 currents by 90% at 24 µg/ml in a dose-dependent manner while decreasing store-operated calcium entry to 56% at only 2.4 µg/ml. mAb82 decreased PCa survival rate in vitro by 71% at 12 µg/ml via inducing cell death through the apoptosis cascade via activation of the protease calpain, following bax activation, mitochondria enlargement, and loss of cristae, Cyt C release, pro-caspase 9 cleavage with the subsequent activation of caspases 3/7. In vivo, mice bearing either PC3M trpv6+/+ or PC3M trpv6-/- +pTRPV6 tumors were successfully treated with mAb82 at the dose as low as 100 µg/kg resulting in a significant reduction tumor growth by 31% and 90%, respectively. The survival rate was markedly improved by 3.5 times in mice treated with mAb82 in PC3M trpv6+/+ tumor group and completely restored in PC3M trpv6-/- +pTRPV6 tumor group. mAb82 showed a TRPV6-expression dependent organ distribution and virtually no toxicity in the same way as mAbAU1, a control antibody of the same Ig2a isotype. Overall, our data demonstrate for the first time the use of an anti-TRPV6 monoclonal antibody in vitro and in vivo in the treatment of the TRPV6-expressing PCa tumors.

Published
2024
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2. Modelling 3D Tumour Microenvironment In Vivo: A Tool to Predict Cancer Fate

Author

Johanna Marines, Francesca Lorenzini, Karima Kissa, and Laura Fontenille

Subjects
cancer, microenvironment, live imaging, PDX, zebrafish, Biology (General), QH301-705.5
Abstract

Recently, many studies demonstrated the fundamental role of the tumour microenvironment (TME) in cancer progression. Here, we describe a method to visualize in 3D the behaviour of tumours in zebrafish embryos. We highlight two major actors of the TME, macrophages and vessels. This valuable tool is transposable to Patient-Derived Xenograft imaging in order to predict the fate of malignant tumours according to the dynamics of their TME.

Published
2023
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3. Improving the response to oxaliplatin by targeting chemotherapy-induced CLDN1 in resistant metastatic colorectal cancer cells

Author

Sara Cherradi, Véronique Garambois, Johanna Marines, Augusto Faria Andrade, Alexandra Fauvre, Olivia Morand, Manon Fargal, Ferial Mancouri, Adeline Ayrolles-Torro, Nadia Vezzo-Vié, Marta Jarlier, Gerald Loussaint, Steve Huvelle, Nicolas Joubert, Thibault Mazard, Céline Gongora, Philippe Pourquier, Florence Boissière-Michot, and Maguy Del Rio

Subjects
Colorectal cancer, CLDN1, ADC, Chemotherapy, Resistance, “One-two punch”, Biotechnology, TP248.13-248.65, Biology (General), QH301-705.5, Biochemistry, QD415-436
Abstract

Abstract Background Tumor resistance is a frequent cause of therapy failure and remains a major challenge for the long-term management of colorectal cancer (CRC). The aim of this study was to determine the implication of the tight junctional protein claudin 1 (CLDN1) in the acquired resistance to chemotherapy. Methods Immunohistochemistry was used to determine CLDN1 expression in post-chemotherapy liver metastases from 58 CRC patients. The effects of oxaliplatin on membrane CLDN1 expression were evaluated by flow cytometry, immunofluorescence and western blotting experiments in vitro and in vivo. Phosphoproteome analyses, proximity ligation and luciferase reporter assays were used to unravel the mechanism of CLDN1 induction. RNAseq experiments were performed on oxaliplatin-resistant cell lines to investigate the role of CLDN1 in chemoresistance. The “one-two punch” sequential combination of oxaliplatin followed by an anti-CLDN1 antibody-drug conjugate (ADC) was tested in both CRC cell lines and murine models. Results We found a significant correlation between CLDN1 expression level and histologic response to chemotherapy, CLDN1 expression being the highest in resistant metastatic residual cells of patients showing minor responses. Moreover, in both murine xenograft model and CRC cell lines, CLDN1 expression was upregulated after exposure to conventional chemotherapies used in CRC treatment. CLDN1 overexpression was, at least in part, functionally related to the activation of the MAPKp38/GSK3β/Wnt/β-catenin pathway. Overexpression of CLDN1 was also observed in oxaliplatin-resistant CRC cell lines and was associated with resistance to apoptosis, suggesting an anti-apoptotic role for CLDN1. Finally, we demonstrated that the sequential treatment with oxaliplatin followed by an anti-CLDN1 ADC displayed a synergistic effect in vitro and in in vivo. Conclusion Our study identifies CLDN1 as a new biomarker of acquired resistance to chemotherapy in CRC patients and suggests that a “one-two punch” approach targeting chemotherapy-induced CLDN1 expression may represent a therapeutic opportunity to circumvent resistance and to improve the outcome of patients with advanced CRC.

Published
2023
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4. Nucleic Acid Immunity and DNA Damage Response: New Friends and Old Foes

Author

Clara Taffoni, Alizée Steer, Johanna Marines, Hanane Chamma, Isabelle K. Vila, and Nadine Laguette

Subjects
cytosolic nucleic acids, DNA damage responses, inflammation, cGAS-STING, IFI16, DNA-PK, Immunologic diseases. Allergy, RC581-607
Abstract

The maintenance of genomic stability in multicellular organisms relies on the DNA damage response (DDR). The DDR encompasses several interconnected pathways that cooperate to ensure the repair of genomic lesions. Besides their repair functions, several DDR proteins have emerged as involved in the onset of inflammatory responses. In particular, several actors of the DDR have been reported to elicit innate immune activation upon detection of cytosolic pathological nucleic acids. Conversely, pattern recognition receptors (PRRs), initially described as dedicated to the detection of cytosolic immune-stimulatory nucleic acids, have been found to regulate DDR. Thus, although initially described as operating in specific subcellular localizations, actors of the DDR and nucleic acid immune sensors may be involved in interconnected pathways, likely influencing the efficiency of one another. Within this mini review, we discuss evidences for the crosstalk between PRRs and actors of the DDR. For this purpose, we mainly focus on cyclic GMP-AMP (cGAMP) synthetase (cGAS) and Interferon Gamma Inducible Protein 16 (IFI16), as major PRRs involved in the detection of aberrant nucleic acid species, and components of the DNA-dependent protein kinase (DNA-PK) complex, involved in the repair of double strand breaks that were recently described to qualify as potential PRRs. Finally, we discuss how the crosstalk between DDR and nucleic acid-associated Interferon responses cooperate for the fine-tuning of innate immune activation, and therefore dictate pathological outcomes. Understanding the molecular determinants of such cooperation will be paramount to the design of future therapeutic approaches.

Published
2021
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5. <scp>DNA</scp> damage repair kinase <scp>DNA‐PK</scp> and <scp>cGAS</scp> synergize to induce cancer‐related inflammation in glioblastoma

Author

Clara Taffoni, Johanna Marines, Hanane Chamma, Soumyabrata Guha, Mathilde Saccas, Amel Bouzid, Ana‐Luiza Chaves Valadao, Clément Maghe, Jane Jardine, Mi Kyung Park, Katarzyna Polak, Mara De Martino, Claire Vanpouille‐Box, Maguy Del Rio, Celine Gongora, Julie Gavard, Nicolas Bidère, Min Sup Song, Donovan Pineau, Jean‐Philippe Hugnot, Karima Kissa, Laura Fontenille, Fabien P Blanchet, Isabelle K Vila, Nadine Laguette, Institut de génétique humaine (IGH), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), AZELEAD, Signaling in Oncogenesis, Angiogenesis and Permeability - SOAP (CRCI2NA / Eq 6), Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes-Angers (CRCI2NA ), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), The University of Texas M.D. Anderson Cancer Center [Houston], Weill Cornell Medicine [Cornell University], Cornell University [New York], Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Laboratory of Pathogen and Host Immunity [Montpellier] (LPHI), Institut de Recherche en Infectiologie de Montpellier (IRIM), ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), European Project: 637763,H2020,ERC-2014-STG,CrIC(2015), and European Project: 893772,DIM-CrIC

Subjects
DNA-PK, General Immunology and Microbiology, inflammation, [SDV]Life Sciences [q-bio], General Neuroscience, [SDV.IMM]Life Sciences [q-bio]/Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Molecular Biology, tumor immunogenicity, General Biochemistry, Genetics and Molecular Biology, cGAS
Abstract

International audience; Cytosolic DNA promotes inflammatory responses upon detection by the cyclic GMP-AMP (cGAMP) synthase (cGAS). It has been suggested that cGAS downregulation is an immune escape strategy harnessed by tumor cells. Here, we used glioblastoma cells that show undetectable cGAS levels to address if alternative DNA detection pathways can promote pro-inflammatory signaling. We show that the DNA-PK DNA repair complex (i) drives cGAS-independent IRF3-mediated type I Interferon responses and (ii) that its catalytic activity is required for cGAS-dependent cGAMP production and optimal downstream signaling. We further show that the cooperation between DNA-PK and cGAS favors the expression of chemokines that promote macrophage recruitment in the tumor microenvironment in a glioblastoma model, a process that impairs early tumorigenesis but correlates with poor outcome in glioblastoma patients. Thus, our study supports that cGAS-dependent signaling is acquired during tumorigenesis and that cGAS and DNA-PK activities should be analyzed concertedly to predict the impact of strategies aiming to boost tumor immunogenicity.

Published
2022

6. The crosstalk between DNA-PK and cGAS drives tumor immunogenicity

Author

Clara Taffoni, Johanna Marines, Hanane Chamma, Mathilde Saccas, Amel Bouzid, Soumyabrata Guha, Ana-Luiza Chaves Valadao, Katarzyna Polak, Maguy Del Rio, Celine Gongora, Donovan Pineau, Jean-Philippe Hugnot, Karima Kissa, Laura Fontenille, Fabien P. Blanchet, Isabelle K. Vila, and Nadine Laguette

Abstract

SUMMARYCytosolic DNAs promote inflammatory responses upon detection by the cyclic GMP-AMP (cGAMP) synthase (cGAS). It has been thus suggested that cGAS downregulation is an immune escape strategy harnessed by tumor cells. Here, we used glioblastoma cells that lack cGAS to question whether alternative DNA detection pathways can promote pro-inflammatory signaling. We show that the DNA-PK DNA repair complex drives cGAS independent inflammatory responses but that its catalytic activity is required for cGAS-dependent cGAMP production and optimal downstream signaling. We further show that the cooperation between DNA-PK and cGAS favors the expression of chemokines that promote macrophage recruitment in the tumor microenvironment, a process that impaired early tumorigenesis but correlated with poor outcome. Thus, our study supports that cGAS-dependent signaling is acquired during tumorigenesis and that cGAS and DNA-PK activities should be analyzed concertedly to predict the impact of strategies aiming to boost tumor immunogenicity.

Published
2022

7. Sting orchestrates the crosstalk between polyunsaturated fatty acids metabolism and inflammatory responses

Author

Xavier Bonnefont, Andrei Turtoi, Hanane Chamma, Alizée Steer, Isabelle K. Vila, Johanna Marines, Dimitrios Vlachakis, Nadine Laguette, Mathilde Saccas, Clara Taffoni, Lei Jin, Line S. Reinert, Søren R. Paludan, and Evgenia Turtoi

Subjects
chemistry.chemical_classification, 0303 health sciences, FADS2, Inflammation, Biology, eye diseases, Cell biology, 03 medical and health sciences, Sting, 0302 clinical medicine, Immune system, Fatty acid desaturase, chemistry, 030220 oncology & carcinogenesis, Stimulator of interferon genes, medicine, biology.protein, medicine.symptom, Homeostasis, 030304 developmental biology, Polyunsaturated fatty acid
Abstract

SummaryInflammatory disorders are major health issues in which immune function and metabolic homeostasis are concertedly altered. Yet, the molecular mechanisms coordinating innate and metabolic pathways in homeostatic conditions are poorly understood. Here, we unveil a negative regulatory feedback loop involving the Stimulator of interferon genes (Sting) and the Fatty acid desaturase 2 (Fads2). At steady state, Sting regulates FA metabolism by repressing the activity of the Fads2 enzyme responsible for the desaturation of polyunsaturated FAs (PUFAs). Importantly, Sting activation increased Fads2 activity, while antagonizing Fads2 enhanced Sting activation, promoting the establishment of an anti-viral state. Remarkably, the cross-regulation between Sting and Fads2 is mediated by the cyclic GMP-AMP (cGAMP) Sting agonist and PUFAs. Indeed, we found that PUFAs inhibit Sting activation, while Sting agonists bind Fads2. Thus, our study identifies Sting as a master regulator of FA metabolism, and PUFAs as modulators of Sting-dependent inflammation. The interplay between Fads2 and Sting determines the fine-tuning of inflammatory responses, but comes at the expense of metabolic alterations, which are critical to consider in human pathologies associated with aberrant Sting activation.

Published
2020

8. STING orchestrates the crosstalk between polyunsaturated fatty acid metabolism and inflammatory responses

Author

Isabelle K. Vila, Hanane Chamma, Alizée Steer, Mathilde Saccas, Clara Taffoni, Evgenia Turtoi, Line S. Reinert, Saqib Hussain, Johanna Marines, Lei Jin, Xavier Bonnefont, Mathieu Hubert, Olivier Schwartz, Soren R. Paludan, Gaetan Van Simaeys, Gilles Doumont, Bijan Sobhian, Dimitrios Vlachakis, Andrei Turtoi, Nadine Laguette, Institut de génétique humaine (IGH), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), BioCampus (BCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Aarhus University [Aarhus], Albany Medical College, Institut de Génomique Fonctionnelle (IGF), Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Aarhus University Hospital, Center for Microscopy and Molecular Imaging (IBMM - CMMI), Université libre de Bruxelles (ULB), Agricultural University of Athens, Biomedical Research Foundation of the Academy of Athens (BRFAA), National and Kapodistrian University of Athens (NKUA), We acknowledge the SIRIC Montpellier Cancer grant (INCa_Inserm_DGOS_12553), Metamus-RAM and iExplore-RAM animal facilities, the Laboratoire de Mesures Physiques of the University of Montpellier for access to the MS instruments, the MRI imaging facility, member of the national infrastructure France-BioImaging infrastructure supported by the French National Research Agency (ANR-10-INBS-04, 'Investments for the future'), and Ross Tomaino from the Taplin Mass Spectrometry Facility of Harvard Medical School for MS analysis. We thank T. Emilien, A. Sedda, C. de Maeseneire, N. Passon, and C. Van Heymbeek for their contribution. We thank the Cyclotron team from the Erasme Hospital, Brussels, Belgium, for the FDG provision. Work in N.L.’s laboratory is supported by the European Research Council (ERC-Stg CrIC: 637763, ERC-PoC DIM-CrIC: 893772), la Ligue pour la Recherche contre le Cancer, and the Agence Nationale de Recherche sur le Sida et les Hépatites Virales (ANRS: ECTZ117448). H.C. is supported by a PhD fellowship from la Ligue pour la Recherche contre le Cancer. C.T. is supported by the Merck Sharp and Dohme Avenir (MSD-Avenir – GnoSTic) program and an ANRS fellowship (ECTZ119088). J.M. is supported by a Conventions Industrielles de Formation par la Recherche (CIFRE) fellowship from the Agence Nationale de Recherche Technologie (ANRT). A.S. is supported by the ERC-PoC DIM-CrIC (893772). I.K.V. is supported by the ERC-Stg CrIC (637763) and the Fondation pour la Recherche Médicale (ARF20170938586). Work in S.R.P.’s laboratory is supported by the European Research Council (ERC-AdG ENVISION, 786602), the Novo Nordisk Foundation (NNF18OC0030274), and the Lundbeck Foundation (R198-2015-171 and R268-2016-3927). Work in A.T.’s laboratory is supported by a SIRIC Montpellier Cancer grant (INCa_Inserm_DGOS_12553), the Fondation de France (grant no. 00078461), and a LabEx MabImprove Starting Grant. X.B. is supported by ANR GH-gen (ANR-18-CE14-0017). The Center for Microscopy and Molecular Imaging (CMMI) is supported by the European Regional Development Fund (ERDF), the Walloon Region, the Fondation ULB, the Fonds Erasme, and Association Vinçotte Nuclear (AVN). G.D. is supported by the European Regional Development Fund (ERDF) and the Walloon Region. Work in O.S.’s lab is funded by Institut Pasteur, Urgence COVID-19 Fundraising Campaign of Institut Pasteur, ANRS, the Vaccine Research Institute (ANR-10-LABX-77), Labex IBEID (ANR-10-LABX-62-IBEID), ANR/FRM Flash Covid PROTEO-SARS-CoV-2, and IDISCOVR, Fondation pour la Recherche Médicale. Schematic representations were created with https://biorender.com, We thank M. Benkirane, G. Cavalli, J. Déjardin, and B. de Massy for discussions and comments. We thank C. Goujon and B. Bonaventure for CRISPR/Cas9 gRNA sequences., ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), ANR-10-LABX-0053,MAbImprove,Optimization of therapeutic monoclonal antibodies development Better antibodies, better developed AND better used(2010), ANR-18-CE14-0017,GH-Gen,Origine et fonction du generateur hypophysaire de pulses d'hormone de croissance(2018), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-10-LABX-0077,VRI,Initiative for the creation of a Vaccine Research Institute(2010), ANR-20-COVI-0062,proteoCOVID,Protéomique clinique de la protéine SARS-CoV-2 Spike pour optimiser sa détection et le développement de tests sérologiques(2020), European Project: 637763,H2020,ERC-2014-STG,CrIC(2015), European Project: 893772,DIM-CrIC, European Project: 786602,ENVISION, Virus et Immunité - Virus and immunity, Guerineau, Nathalie C., Développment d'une infrastructure française distribuée coordonnée - - France-BioImaging2010 - ANR-10-INBS-0004 - INBS - VALID, Laboratoires d'excellence - Optimization of therapeutic monoclonal antibodies development Better antibodies, better developed AND better used - - MAbImprove2010 - ANR-10-LABX-0053 - LABX - VALID, APPEL À PROJETS GÉNÉRIQUE 2018 - Origine et fonction du generateur hypophysaire de pulses d'hormone de croissance - - GH-Gen2018 - ANR-18-CE14-0017 - AAPG2018 - VALID, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, Laboratoires d'excellence - Initiative for the creation of a Vaccine Research Institute - - VRI2010 - ANR-10-LABX-0077 - LABX - VALID, Protéomique clinique de la protéine SARS-CoV-2 Spike pour optimiser sa détection et le développement de tests sérologiques - - proteoCOVID2020 - ANR-20-COVI-0062 - COVID-19 - VALID, Molecular basis of the cross-talk between chronic inflammation and cancer - CrIC - - H20202015-04-01 - 2020-03-31 - 637763 - VALID, Decreasing Pancreatic Adenocarcinoma-related Inflammation using small molecule inhibitors of STING - DIM-CrIC - 893772 - INCOMING, Novel mechanisms of early defense against virus infections - ENVISION - 786602 - INCOMING, Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), BioCampus Montpellier (BCM), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), AZELEAD, 377 Rue du Professeur Blayac, 34080 Montpellier, France, Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)

Subjects
Fatty Acid Desaturases, Physiology, [SDV]Life Sciences [q-bio], nucleic acid immunity, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, cytosolic DNA, Article, 03 medical and health sciences, 0302 clinical medicine, delta-6 Desaturase, Humans, FADS2, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Molecular Biology, 030304 developmental biology, Inflammation, Metabolic Syndrome, interferon responses, 0303 health sciences, Cell Biology, Lipid Metabolism, eye diseases, 3. Good health, [SDV] Life Sciences [q-bio], Fatty Acids, Unsaturated/metabolism, inflammation, 030220 oncology & carcinogenesis, Fatty Acids, Unsaturated, metabolism, Fatty Acid Desaturases/genetics, STING, cGAS, polyunsaturated fatty acids
Abstract

Summary Concerted alteration of immune and metabolic homeostasis underlies several inflammation-related pathologies, ranging from metabolic syndrome to infectious diseases. Here, we explored the coordination of nucleic acid-dependent inflammatory responses and metabolic homeostasis. We reveal that the STING (stimulator of interferon genes) protein regulates metabolic homeostasis through inhibition of the fatty acid desaturase 2 (FADS2) rate-limiting enzyme in polyunsaturated fatty acid (PUFA) desaturation. STING ablation and agonist-mediated degradation increased FADS2-associated desaturase activity and led to accumulation of PUFA derivatives that drive thermogenesis. STING agonists directly activated FADS2-dependent desaturation, promoting metabolic alterations. PUFAs in turn inhibited STING, thereby regulating antiviral responses and contributing to resolving STING-associated inflammation. Thus, we have unveiled a negative regulatory feedback loop between STING and FADS2 that fine-tunes inflammatory responses. Our results highlight the role of metabolic alterations in human pathologies associated with aberrant STING activation and STING-targeting therapies., Graphical abstract, Highlights • STING inhibits FADS2-dependent desaturation of PUFAs and LC-PUFAs • STING activation leads to upregulation of FADS2-associated desaturase activity • STING agonists activate FADS2-dependent PUFA and LC-PUFA desaturation • PUFAs inhibit STING-dependent inflammatory responses, The stimulator of interferon genes (STING) is a central regulator of nucleic acid-associated inflammatory responses. Here, Vila et al. discover that STING regulates polyunsaturated fatty acid (PUFA) metabolism, and in turn, PUFAs inhibit STING-dependent inflammation. This cross-regulation is central to the maintenance of metabolic homeostasis.

Published
2022

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