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- Title
Essential role of hyperacetylated microtubules in innate immunity escape orchestrated by the EBV-encoded BHRF1 protein.
- Authors
Glon, Damien; Vilmen, Géraldine; Perdiz, Daniel; Hernandez, Eva; Beauclair, Guillaume; Quignon, Frédérique; Berlioz-Torrent, Clarisse; Maréchal, Vincent; Poüs, Christian; Lussignol, Marion; Esclatine, Audrey
- Abstract
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. Author summary: Viruses have developed numerous strategies to ensure their persistence in the host, notably by counteracting the innate immune system. The Epstein-Barr virus (EBV), which infects most humans worldwide, encodes a mitochondria and ER-localized protein named BHRF1, which participates in this viral persistence. Indeed, we have recently demonstrated that BHRF1, in addition to its well-described anti-apoptotic activity, has the ability to stimulate autophagy and to inhibit interferon (IFN) response. In this new study, we decipher the original mechanism used by BHRF1 to dampen antiviral immunity. We uncovered that a post-translational modification of the microtubule (MT) network induced by BHRF1 regulates IFN production. To do so, BHRF1 interacts with a cellular acetyltransferase called ATAT1 to increase the acetylation level of MT. One of the consequences of this MT modification is the clustering of autophagosomes and mitochondria in a juxtanuclear region. The sequestration of mitochondria inside the autophagosomes leads to the induction of mitophagy and blocks the signalling pathway triggering IFN production. Finally, we demonstrate that this mechanism, dependent on MT acetylation, occurs during EBV reactivation.
- Subjects
NATURAL immunity; GENE expression; MITOCHONDRIAL proteins; VIRAL proteins; POST-translational modification; MICROTUBULES
- Publication
PLoS Pathogens, 2022, Vol 18, Issue 3, p1
- ISSN
1553-7366
- Publication type
Article
- DOI
10.1371/journal.ppat.1010371