I2BC Paris-Saclay

Autophagy receptor T6BP (TAX1BP1) stabilizes the invariant chain (CD74) and regulates MHC-II molecule (MHC-II) trafficking, thereby favouring the presentation of high affinity peptides to virus-specific CD4+ T cells.

CD4+ T cells play a major role in establishing and maintaining antiviral immunity. They determine, in particular, the quality of antibody responses to viruses. CD4+ T cells are activated by antigenic peptides derived from extracellular or newly synthesized (endogenous) viral proteins presented by MHC-II molecules on the cell surface. The pathways leading to the processing and presentation of endogenous antigens remain poorly characterized.
Here, we hypothesize that the so-called autophagy receptors (AR) may contribute at various, so far unknown, levels to MHC II-restricted viral antigen presentation. We demonstrate that the AR, TAX1BP1, promotes endogenous presentation of HIV- and HCMV-derived peptides. In fact, the role of TAX1BP1 is not limited to viral antigens since the global repertoire of peptides presented by MHC-II molecules is dramatically changed upon TAX1BP1 silencing. We show that TAX1BP1 silencing induces a relocalization of MHC-II peptide-loading compartments, the generation of unstable MHC-II-peptide complexes and a rapid degradation of the invariant chain CD74, which might directly influence the quality of the MHC-II peptide repertoire.
To get a hint on possible mechanisms, we defined the interactome of TAX1BP1 and identified novel protein partners that potentially participate in the TAX1BP1-mediated regulation of MHC-II peptide loading complexes, amongst them the ER chaperone calnexin (CANX). We show that TAX1BP1 binds the cytoplasmic tail of CANX, which regulates its ER functions. Finally, we provide the direct demonstration that silencing CANX also induces CD74 degradation and decreases the ability of cells to activate antiviral CD4+ T cells.
Altogether, this study identifies TAX1BP1 as a key player in MHC-II-restricted antigen presentation and CD4+ T cell immunity. We are currently asking whether viruses might target TAX1BP1 to escape immune responses.

More information: here

Contact: Arnaud Moris <arnaud.moris@i2bc.paris-saclay.fr>

The GO Paris-Saclay 2021 team won a gold medal and the "Best Inclusivity" prize at the iGEM 2021 international synthetic biology competition on Sunday, November 14.

The team's project "EndoSeek" aims to develop a new diagnostic tool for endometriosis, which is a painful and poorly understood pathology caused by the proliferation of uterine cells outside the uterus. Worldwide, this disease affects about 10% of women and can take up to 7 years to diagnose. Based on preliminary studies using small patient cohorts, certain blood microRNAs (miRNAs) may be biomarkers of the disease.
The team has developed a machine learning program that will allow identification of new endometriosis biomarkers with future cohorts. In experiments conducted this summer at I2BC, students exploited Cas13a and Cas14a1 nucleases for miRNA detection. They created a video game to educate adults and children over the age of 10 about endometriosis and synthetic biology. Finally, following their dialogue with patients and physicians, they questioned the ethical implications of diagnostics.
The team was awarded the Best Inclusivity Award for outstanding efforts to include people with diverse identities. The students thought about the position of LGBT+ people in their project and created a multi-language, voice-assisted website with color customization.
This project was supported by the I2BC, the Faculty of Sciences of the University of Paris-Saclay, La Diagonale Paris-Saclay, EUGLOH (European University Alliance for Global Health), the Graduate School Life Sciences and Health, IDT and Promega.

Team 2021 supervisors included Téo Hébra (ICSN) and 5 members of the I2BC: Philippe Bouloc, Stéphanie Bury-Moné, Emma Piattelli, Ombeline Rossier and Charlène Valadon.
For more information, see the wiki https://2021.igem.org/Team:GO_Paris-Saclay and the video https://video.igem.org/w/ihqYR3UfveimEtZVv7x6jE.

BHRF1, a multifunctional viral protein expressed during Epstein-Barr virus reactivation, modulates mitochondrial dynamics and induces MT hyperacetylation to escape innate immunity. Moreover, the loss of MT hyperacetylation impedes BHRF1 to initiate mitophagy, which is essential to inhibit the signaling pathway.

Innate immunity constitutes the first line of defense against viruses, in which mitochondria play an important role in the induction of the interferon (IFN) response. BHRF1, a multifunctional viral protein expressed during Epstein-Barr virus reactivation, modulates mitochondrial dynamics and disrupts the IFN signaling pathway. Mitochondria are mobile organelles that move through the cytoplasm thanks to the cytoskeleton and in particular the microtubule (MT) network. MTs undergo various post-translational modifications, among them tubulin acetylation. In this study, we demonstrated that BHRF1 induces MT hyperacetylation to escape innate immunity. Indeed, the expression of BHRF1 induces the clustering of shortened mitochondria next to the nucleus. This "mito-aggresome" is organized around the centrosome and its formation is MT-dependent. We also observed that the α-tubulin acetyltransferase ATAT1 interacts with BHRF1. Using ATAT1 knockdown or a non-acetylatable α-tubulin mutant, we demonstrated that this hyperacetylation is necessary for the mito-aggresome formation. Similar results were observed during EBV reactivation. We investigated the mechanism leading to the clustering of mitochondria, and we identified dyneins as motors that are required for mitochondrial clustering. Finally, we demonstrated that BHRF1 needs MT hyperacetylation to block the induction of the IFN response. Moreover, the loss of MT hyperacetylation blocks the localization of autophagosomes close to the mito-aggresome, impeding BHRF1 to initiate mitophagy, which is essential to inhibiting the signaling pathway. Therefore, our results reveal the role of the MT network, and its acetylation level, in the induction of a pro-viral mitophagy.

More information: https://journals.plos.org/plospathogens/article/authors?id=10.1371/journal.ppat.1010371

contact: Audrey ESCLATINE <audrey.esclatine@i2bc.paris-saclay.fr>

A PhD student (Université Paris-Saclay) unveils her comic strip, illustrated by Marine Spaak, and invites you to dive into the heart of scientific research on HIV !

Like the book "Sciences en bulles", presented at the "Fête de la Science", the "Diagonale Paris-Saclay" challenged our doctoral student, Lisa Bertrand, to explain and share her thesis in a fun way in the form of a comic strip. His topic? Defining the translatome of HIV-1 in order to identify new antigens recognized by T-cells.
She followed several introductory sessions that taught her how to synthesize her ideas, turn them into a playful script, choose illustrations to complete her remarks, until she got a first storyboard. The illustrator Marine Spaak accompanied her throughout this process and then took it upon herself to shape all these ideas! Discover their image and immerse yourself in the world of the ribosome, a small cellular constituent responsible for protein production.You will find there that the AIDS virus hijacks ribosomes for its own benefit to make its own viral proteins. And how French research explores this phenomenon, in order to develop therapies. In addition to therapeutic research, the study of viruses is an excellent tool for understanding the functioning of the cell.
The comic on :
http://www.sciencesociete.universite-paris-saclay.fr/decouvrir/la-recherche-sort-de-sa-bulle/#section_3

Uncovering the complete building plan and assembly pathway of a viral DNA delivery device

Siphoviruses are the major killers of bacteria. A long non-contractile tail is the key device of these bacteriophages to recognize specifically the host cell and to deliver their viral dsDNA to the bacterial cytoplasm. Furthermore, bacteria use nanotubes homologous to phage long tails to attack other cells. Although structures of these megadalton protein complexes are available, significantly less is known on the molecular mechanisms leading to their assembly.

In a study published in J Mol Biol, I2BC researchers and their collaborators have undertaken a comprehensive analysis of the complete molecular organization of the siphovirus SPP1 tail, which infects Bacillus subtilis, and its biogenesis mechanisms. During tail assembly, the association of proteins follows a strict order. This implies that the third component of a complex does not bind until the first two proteins interact together and so on. Characterization of assembly intermediates from mutants deficient in each of the tail components revealed the sequential program of interactions leading to the construction of the SPP1 tail (~6.8 MDa). All proteins engaged, with the probable exception of one (gp22), are required for assembly. They likely represent the minimal protein set required to construct functional long tails. Bioinformatics analysis highlighted the structural plasticity of these tail components, a source of variability and innovation for the functional diversification of this type of nanotube.

More details here

Contact: Isabelle.Auzat or Paulo Tavares

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