Nucleic Acid Immunity and DNA Damage Response: New Friends and Old Foes.
Taffoni C, Steer A, Marines J, Chamma H, Vila IK, Laguette N
Molecular Basis of Inflammation
Molecular bases of human diseases
Inflammation is a normal reaction of the immune system in response to infections or tissue damage. It plays a pivotal role in triggering adaptive immune responses. However, unresolved inflammation is pervasive and fosters several etiologically distinct human pathologies that present with a broad range of symptoms. Such pathologies include cancer, auto-inflammatory and auto-immune disorders, but also metabolic diseases.
The Molecular Basis of Inflammation team studies the molecular mechanisms involved in the initiation, maintenance, and resolution of inflammation. To decipher how deregulation of these processes promote pathologies, we study inflammatory responses at several scales:
- At the molecular level: we identify and characterize new pathways involved in triggering inflammatory pathologies,
- At the cellular level: we characterize how these pathways are regulated depending on cellular identity,
- At the tissue level: we study how cellular heterogeneity within tissues dictates the outcome of inflammatory response and impacts homeostasis
- At the organism level: we study inflammatory responses and the consequences of their pathological activation on integrated in vivo models .
To achieve these aims, the Molecular Basis of Inflammation team uses and develops techniques ranging from nanotechnologies, single-cell transcriptomics, to in vivo phenotyping. We develop interdisciplinary approaches around these themes through networks and collaborations at national (https://www.innasco.fr/) and international (https://frontinov.cnrs.fr/) levels.
The “Molecular Basis of Inflammation” team welcomes applications from research scientists and engineers willing to implement new technologies in a fast-evolving area of research.
Contact: Nadine.Laguette@igh.cnrs.fr
PUBLICATIONS OF THE TEAM
Sting orchestrates the crosstalk between polyunsaturated fatty acids metabolism and inflammatory responses
Isabelle K. Vila, Hanane Chamma, Alizée Steer, Clara Taffoni, Line S. Reinert, Evgenia Turtoi, Mathilde Saccas, Johanna Marines, Lei Jin, Xavier Bonnefont, Soren R. Paludan, Dimitrios Vlachakis, Andrei Turtoi, Nadine Laguette
Animal Models for the Study of Nucleic Acid Immunity: Novel Tools and New Perspectives
Isabelle K Vila , Maxence Fretaud , Dimitrios Vlachakis, Nadine Laguette, Christelle Langevin
Lysyl-tRNA synthetase produces diadenosine tetraphosphate to curb STING-dependent inflammation
J. Guerra, A.-L. Valadao, D. Vlachakis, K. Polak, I. K. Vila, C. Taffoni, T. Prabakaran, A. S. Marriott, R. Kaczmarek, A. Houel, B. Auzemery,S. Déjardin,P. Boudinot, B. Nawrot, N. J. Jones, S. R. Paludan, S. Kossida, C. Langevin and N. Laguette
V1b vasopressin receptor trafficking and signaling: Role of arrestins, G proteins and Src kinase.
Perkovska S, Méjean C, Ayoub MA, Li J, Hemery F, Corbani M, Laguette N, Ventura MA, Orcel H, Durroux T, Mouillac B, Mendre C
Upregulated LINE-1 Activity in the Fanconi Anemia Cancer Susceptibility Syndrome Leads to Spontaneous Pro-inflammatory Cytokine Production
Bregnard, C, Guerra, J, Dejardin, S, Passalacqua, F, Benkirane, M, Laguette, N
Shaping of the host cell by viral accessory proteins
Laguette N, Benkirane M.
DNA damage repair machinery and HIV escape from innate immune sensing
Brégnard C, Benkirane M, Laguette N.
PUBLICATIONS COMMUNES
Premature Activation of the SLX4 Complex by Vpr Promotes G2/M Arrest and Escape from Innate Immune Sensing
Laguette,N., Bregnard, C., Hue, P., Basbous, J., Yatim, A., Larroque, M., Kirchhoff, F., Constantinou, A., Sobhian, B., Benkirane, M.
2014 - CELL
, 156, 1-2, 134-145 24412650 
Service porteur :
Laboratory of Molecular Virology
Projects developed by the team include:
Detection and regulation of cytosolic DNA:RNA hybrids
We have shown that the reverse transcription (RT) activity associated with endogenous retroelements generates immunogenic nucleic acids. These nucleic acids are recognized via the cGAS-STING pathway, central to the detection of cytosolic nucleic acids. Activation of this signaling pathway feeds chronic inflammation associated with the Fanconi Anemia cancer predisposition syndrome (Brégnard et al. EBioMed, 2016).
We next focused on identifying pathways regulating RT-generated immunogenic nucleic acids - in particular DNA:RNA hybrids. We have identified the Lysyl-tRNA synthetase (LysRS), a key player in the translation of proteins, as involved in the regulation of inflammation associated with the cytosolic DNA:RNA hybrids (Guerra et al. Science Adv, 2020).
Currently, we are studying the impact of LysRS on tumorigenesis.
Novel cytosolic nucleic acids detection routes
Genotoxic stress is a complex phenomenon engaging numerous molecular interactions and post-translational modifications, induced by genetic instability and DNA replication stress. Genotoxic stress response proteins are direct regulators of the innate immune response via (i) their ability to recognize non-canonical nucleic acid structures, including endogenous DNAs present in the cytosol, and (ii) regulation of DNA repair. There is ample evidence to suggest the existence of DNA recognition pathways distinct from the canonical cGAS-STING pathway and that operate in a tissue or cell type-dependent manner. We use a range of in vivo and in vitro techniques to identify these novel DNA recognition pathways, their interconnection with canonical pathways, and their impact on the activation of anti-tumor immune responses.
Inflammation and metabolism
Chronic inflammation can be fueled by high fat diets that promote concerted alterations of inflammatory and metabolic pathways. We recently identified the STING protein, central to the production of type I Interferons in the presnece of cytosolic nucleic acids, as a central regulator of polyunsaturated fatty acid metabolism. We are exploring the communication between these inflammatory and metabolic pathways, at the cellular, tissue and body levels, to reveal their impact on the maintenance of homeostasis and in chronic inflammatory pathologies (Vila et al. https://www.biorxiv.org/content/10.1101/2020.12.22.423950v1.)
Chromatinian control of inflammatory responses
Although most immunogenic nucleic acids are detected in the cytosol, the proteins mediating this recognition are, to a large extent, associated with chromatin when inactive. This for example the case of the cGAS protein, central to the detection of nucleic acids in the cytosol. Our recent work shows that the cytosolic presence of immunogenic nucleic acids leads to the mobilization of numerous chromatinian proteins. We study the consequences of cytosolic mobilization of nuclear proteins and their impact on the regulation of inflammatory responses.
Collaborativ projects
Supervisor: Hanane CHAMMA
Title: Identification of new regulators of immunity to pathological nucleic acids
Direction : Dr. Nadine Laguette
Date of defense: December 2022
Members of the defense jury : not yet defined
Supervisor : Johanna MARINES
Title : Impact of cytosolic nucleic acids on antitumor immunity in a glioblastoma model
Direction : Dr. Karima Kissa & Dr. Nadine Laguette
Date of defense: December 2021
Members of the defense jury: not yet defined
Education/Academic Positions
2015 - Group Leader – Molecular basis of Cancer-Related Inflammation Lab., IGH (UPR 1142), Montpellier, France
2014 - HDR at University of Montpellier I, France
2012-2014 - CR2 CNRS – Molecular Virology Lab., IGH (UPR 1142), Montpellier, France
2009-2012 - Postdoc – Molecular Virology Lab, IGH (UPR 1142), Montpellier, France
2005–2008 - PhD in Cell Biology – Cochin Institute, University Paris V, France
2004–2005 - Master2 in Cell Biology – University of Paris V, France
2003–2004 - Master1 in Cell Biology and Physiology – University of Paris XI, France
2000–2003 - BSc in Molecular Biology and Genetics – RHUL, London, UK
Awards
2021 - CNRS Bronze Medal
2019 - ERC Proof of Concept
2015 - “Georges Frêche – Université Sud de France” Award
2015 - ERC Starting Grant
2014 - Sanofi-Pasteur Institute Young Investigator Award
2013 - CNRS “Prime d’Excellence Scientifique”
2012 - SIDACTION “Prix jeune chercheur 2012”
2012 - Cold Spring Harbor RETROVIRUSES Meeting “Andy Kaplan Prize”
2012 - French Academy of Science : “Les grandes avancées françaises 2011-2012 en biologie présentées par leurs auteurs”
Molecular basis of the cross-talk between chronic inflammation and cancer*
ERG Starting Grant (CrIC; GA #637763) ~ 1.5 M€ ~ 2015-2021
Synopsis:
The CrIC project aimed at identifying the molecular mechanisms at play in the onset and maintenance of tumor promoting inflammation. Particular interest was brought to inflammation associated with the accumulation of cytosolic nucleic acid species. The latter include ssDNA, dsDNA and RNA:DNA hybrids, that can derive from pathogen infections (viruses, bacteria), but also originate from mitochondria or the nucleus. In recent years, several pathways have been identified as involved in the detection of aberrant cytosolic nucleic acid species. In particular the cyclic GMP-AMP (cGAMP) synthase (cGAS) receptor has been established as one of the key detectors of these moieties, and as a potent inducer of type I Interferon responses. Upon detection of cytosolic nucleic acids, cGAS produces the cGAMP second messenger that can interact with the Stimulator of interferon genes (STING) adaptor protein, leading to the assembly of a STING signalosome that orchestrates type I Interferon responses.
Completion of the objectives set within the proposal has led to:
- insight into ways in which inflammation is initiated within tumor cells. Indeed, we have shown that mobile genetic elements are a source of pathological nucleic acids that are recognized by cGAS to promote chronic type I Interferon production. Indeed, absence of efficient DNA repair through the Fanconi Anemia DNA repair pathway and chemotherapy regimens both lead to de-repression of mobile genetic elements, in particular of the LINE-1 family, that trigger type I Interferon responses (Bregnard et al, EBioMedicine, 2016).
- the identification the Lysyl-tRNA synthetase (LysRS) as a negative regulator of cGAS-STING activation. We have shown that LysRS interacts with RNA:DNA hybrids, preventing their detection by cGAS, but also produces a second messenger (diadenosine tetraphosphate – Ap4A) that interacts with STING, inhibiting the interaction of STING with cGAMP. This control of the cGAS-STING axis, is central to determining the amplitude and duration of type I Interferon responses (Guerra et al, Science Adv; Patent : PCT : WO2021043992). The impact of the identified pathway on tumorigenesis is currently under characterization in the laboratory.
- We have shown that the activation of the cGAS-STING pathway is also controlled by DNA repair proteins, opening novel perspectives in our understanding of how DNA repair and inflammatory pathways contribute to pervasive cancer-associated inflammation (Taffoni et al, Frontiers in Immunology, in press; Taffoni, Marines et al, manuscript in preparation).
- Finally, we demonstrate that STING, independently of its role in inflammatory responses, controls metabolic homeostasis. In particular, we show that STING regulates polyunsaturated fatty acid (PUFAs) metabolism directly, through interacting with the Fatty acid desaturase 2 (Fads2) enzyme and inhibiting its activity. Furthermore, we show that PUFAs exert a negative control on STING activity (Vila et al, bioRXiv).
Work stemming from CrIC has also allowed the team to:
- benefit from an ERC Proof of Concept grant
- to establish an interdisciplinary international research network with leaders in their respective fields (www.frontinov.cnrs.fr)
Publications:
CrIC has so far led to the following publications:
- Vila IK, Chamma H, Steer A, Taffoni C, Reinert LS, Turtoi E, Saccas M, Marines J, Jin L, Bonnefont X, Paludan SR, Vlachakis D, Turtoi A, Laguette N. Control of polyunsaturated fatty acids desaturation by Sting regulates inflammatory responses. bioRXiv. doi: https://doi.org/10.1101/2020.12.22.423950
- Taffoni C, Steer A, Marines J, Chamma H, Vila IK and Laguette N. 2021. Nucleic acid immunity and DNA Damage Response: new friends and old foes. Frontiers in Immunology. https://doi.org/10.3389/fimmu.2021.660560
- Vila IK, Fretaud M, Vlachakis D, Laguette N, Langevin C. 2020. Animal Models for the Study of Nucleic Acid Immunity: Novel Tools and New Perspectives. Journal of molecular biology, Sept 18 2020. https://doi.org/10.1016/j.jmb.2020.08.016
- Guerra J, Valadao A-L, Vlachakis D, Polak K, Vila IK, Prabakaran T, Marriott AS, Kaczmarek R, Houel A, Auzemery B, Déjardin S, Boudinot P, Nawrot B, Jones NJ, Paludan SR, Kossida S, Langevin C, Laguette N. 2020. Lysyl-tRNA synthetase produces diadenosine tetraphosphate to curb STING-dependent inflammation Science Adv. https://doi.org/10.1126/sciadv.aax3333
- Brégnard C, Déjardin S, Passalacqua F, Benkirane M, Laguette N. 2016. Upregulated LINE-1 activity in the Fanconi Anemia cancer susceptibility syndrome leads to spontaneous pro-inflammatory cytokine production. EBioMed. https://doi.org/10.1016/j.ebiom.2016.05.005
Other achievements:
- Creation of the FrontInov International Research Network: https://frontinov.cnrs.fr/
- ERC-Proof-of Concept: Decreasing Pancreatic Adenocarcinoma-related Inflammation using small molecule inhibitors of STING (DIM-CrIC ; GA #893772)
- Patent: STING inhibitors and their therapeutic uses. PCT: WO2021043992.
| * This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement No [637763]) |
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The Molecular Basis of Inflammation Team is thankful to the ERC for supporting the
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