CE15 - Immunologie, Infectiologie et Inflammation

Selective Autophagy Receptors in Downstream Innate Signaling and Antigen Presentation – SARDINN

Submission summary

Initiation of antiviral immune responses requires a coordinate action of innate signaling, including NF-kB and interferon (IFN) pathways, and induction of adaptive immunity, through the processing and presentation of viral antigens by MHC molecules. TAX1BP1, a member of the SQSTM-1-like selective autophagy receptor (SLR) family, regulates both NF-kB and IFN signaling. This SLR is a key effector of mitophagy, involved in the regulation of antiviral signaling, but has also recently emerged as a strong modulator of MHC trafficking and antigen loading. The aim of the SARDINN project is to characterize the multilayered ability of TAX1BP1 to simultaneously regulate innate signaling and antigen presentation, and to interrogate the possible functional redundancy or specificity of TAX1BP1 compared to other SLRs.
Strengthening the idea of a pivotal role of TAX1BP1 in immunity, several viruses directly target TAX1BP1 to manipulate innate signaling. The originality of our approach is to use the HTLV-1 Tax, RSV N and EBV BHRF-1 viral factors, which we identified in our previous work as modulators of TAX1BP1 functions, to define the signaling pathways and molecular mechanisms involved in TAX1BP1/SLR functions.
In a first work package, we will dissect the role of TAX1BP1 and the other SLRs in innate signaling using viral proteins. We will combine the specific expertise of the 3 partners to identify and compare the proximity interactomes of individual SLRs, by a proteomic BioID approach, in the absence or presence of viral protein expression. We will also provide an in-depth characterization of the interaction between SLRs and viral proteins, based on biochemical and imaging approaches (confocal and super-resolution fluorescence microscopy, bimolecular fluorescence complementation). We will then use the properties of these viral factors to characterize the interplay of SLRs with innate signaling pathways and mitophagy, using biochemical as well as innovative imaging approaches including Focused Ion Beam-Scanning Electron Microscopy (FIB-SEM).
In a second work package, we will extend this approach and exploit viral factors as tools to dissect SLR functions in antigen processing and loading onto MHC-II molecules, as well as on MHC-II trafficking. For this, we will perform immunopeptidomics combined to cell imaging and biochemistry.
In this last work package, we will translate these observations into infectious contexts, using in vitro and ex vivo infection models of HTLV-1, EBV and RSV. We will generate a novel conditional TAX1BP1-deficient mouse strain that would limit the deleterious hyper-inflammation observed in Tax1bp1-/- mice, and address the innate immune functions of TAX1BP1 upon in vivo RSV challenge.
The outcome of this project will be a comprehensive map of SLR intricate interactions with innate immunity and antigen presentation, as well as of the underlying molecular mechanisms. We expect that these data will also increase the knowledge of the way viruses (and other pathogens) hijack these pathways during infection.

Project coordinator

Madame Chloé JOURNO (Ecole Normale Supérieure de Lyon)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

I2BC Centre national de la recherche scientifique
CIRI Ecole Normale Supérieure de Lyon
VIM Institut national de recherche pour l'agriculture, l'alimentation et l'environnement

Help of the ANR 682,251 euros
Beginning and duration of the scientific project: January 2023 - 48 Months

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