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.
Highlights
The innate immune system provides the first line of defense against different invading pathogens
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
We demonstrated that BHRF1 disturbs mitochondrial dynamics and subsequently stimulates mitophagy, a cellular process that can sequester and degrade mitochondria by autophagy, leading to the inhibition of type I IFN response by EBV [19]
Summary
The innate immune system provides the first line of defense against different invading pathogens. Mitochondria carry out a crucial role in many cellular processes ranging from energy production to programmed cell death, from calcium homeostasis to cell immunity They constitute a platform for signaling pathways involved in innate immunity thanks to the mitochondrial-resident protein MAVS (mitochondrial antiviral signaling protein), predominantly localized at the mitochondrial outer membrane surface [2,3]. RIG-I (retinoic acidinducible gene) and MDA5 (melanoma differentiation-associated protein 5), two cytoplasmic PRRs that detect viral genomes, are notably translocated to the mitochondria to interact with MAVS that recruits and activates TBK1 (TANK-binding kinase 1). This kinase is required for the phosphorylation of the transcription factors IRF3 and IRF7 (interferon regulatory factors 3 and 7), leading to the subsequent activation of type I IFN promoter [2,3]. The cytoskeleton and notably microtubules (MTs) play a critical role in the distribution of mitochondria throughout the cytoplasm by facilitating their transport to areas with high metabolic demands [4,5]
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