Essential role of hyperacetylated microtubules in innate immunity escape orchestrated by the EBV-encoded BHRF1 protein.

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.

BHRF1, a BCL2 viral homolog, disturbs mitochondrial dynamics and stimulates mitophagy to dampen type I IFN induction.

Mitochondria respond to many cellular functions and act as central hubs in innate immunity against viruses. This response is notably due to their role in the activation of interferon (IFN) signaling pathways through the activity of MAVS (mitochondrial antiviral signaling protein) present at the mitochondrial surface. Here, we report that the BHRF1 protein, a BCL2 homolog encoded by Epstein-Barr virus (EBV), inhibits IFNB/IFN-β induction by targeting the mitochondria.

Early mitochondrial fragmentation is a potential in vitro biomarker of environmental stress.

Mitochondria are essential dynamic organelles that ordinarily balance between fragmentation and fusion. Under stress conditions, a shift toward fragmentation or hyper-fusion is observed as a pro-survival reaction. Fragmentation of mitochondria occurs within minutes or hours after the beginning of the stress and occurs in response to a large number of stress stimuli, including those triggered by environmental contaminants.

Stress-induced hyperacetylation of microtubule enhances mitochondrial fission and modulates the phosphorylation of Drp1 at Ser.

Mitochondria dynamics results from fission and fusion events that may be unbalanced in favor of mitochondrial fragmentation upon cell stress. During oxidative stress, microtubules are hyperacetylated in a mitochondria-dependent manner. In this study, we show that under stress conditions, most of the mitochondria form foci with microtubule domains that carry Drp1.

Reactive oxygen species, AMP-activated protein kinase, and the transcription cofactor p300 regulate α-tubulin acetyltransferase-1 (αTAT-1/MEC-17)-dependent microtubule hyperacetylation during cell stress.

Beyond its presence in stable microtubules, tubulin acetylation can be boosted after UV exposure or after nutrient deprivation, but the mechanisms of microtubule hyperacetylation are still unknown. In this study, we show that this hyperacetylation is a common response to several cellular stresses that involves the stimulation of the major tubulin acetyltransferase MEC-17. We also demonstrate that the acetyltransferase p300 negatively regulates MEC-17 expression and is sequestered on microtubules upon stress.

Autophagy and microtubules - new story, old players.

Both at a basal level and after induction (especially in response to nutrient starvation), the function of autophagy is to allow cells to degrade and recycle damaged organelles, proteins and other biological constituents. Here, we focus on the role microtubules have in autophagosome formation, autophagosome transport across the cytoplasm and in the formation of autolysosomes. Recent insights into the exact relationship between autophagy and microtubules now point to the importance of microtubule dynamics, tubulin post-translational modifications and microtubule motors in the autophagy process.

The ins and outs of tubulin acetylation: more than just a post-translational modification?

Microtubules are highly dynamic polymers of α/β tubulin heterodimers that play key roles in cell division and in organizing cell cytoplasm. Although they have been discovered more than two decades ago, tubulin post-translational modifications recently gained a new interest as their role was increasingly highlighted in neuron differentiation and neurodegenerative disorders. Here, we specifically focus on tubulin acetylation from its discovery to recent studies that provide new insights into how it is regulated in health and disease and how it impacts microtubule functions.

Starvation-induced hyperacetylation of tubulin is required for the stimulation of autophagy by nutrient deprivation.

The molecular mechanisms underlying microtubule participation in autophagy are not known. In this study, we show that starvation-induced autophagosome formation requires the most dynamic microtubule subset. Upon nutrient deprivation, labile microtubules specifically recruit markers of autophagosome formation like class III-phosphatidylinositol kinase, WIPI-1, the Atg12-Atg5 conjugate, and LC3-I, whereas mature autophagosomes may bind to stable microtubules.

Tubulin acetylation favors Hsp90 recruitment to microtubules and stimulates the signaling function of the Hsp90 clients Akt/PKB and p53.

Involved in a wide range of cellular processes such as signal transduction, microtubules are highly dynamic polymers that accumulate various post-translational modifications including polyglutamylation, polyglycylation, carboxyterminal cleavage and acetylation, the functions of which just begin to be uncovered. The molecular chaperone Hsp90, which is essential for the folding and activity of numerous client proteins involved in cell proliferation and apoptosis, associates with the microtubule network but the effects of tubulin post-translational modifications on its microtubule binding has not yet been investigated. Herein, we show that both the constitutive (beta) and the inducible (alpha) Hsp90 isoforms bind to microtubules in a way that depends on the level of tubulin acetylation.

Xenoestrogens modulate genotoxic (UVB)-induced cellular responses in estrogen receptors positive human breast cancer cells.

Human populations and wildlife are exposed to mixtures of both anthropogenic and natural chemicals. Some of these compounds are known to interact principally with the endocrine function, whereas others act mainly on genomic DNA. Given this evidence, we wanted to address the question of whether concomitant exposure of such chemicals was able to interact at the cellular level.

Evaluation of the estrogenic potential of river and treated waters in the Paris area (France) using in vivo and in vitro assays.

For many years, surface waters have been shown to be contaminated by endocrine-disrupting compounds (EDCs), which can cause adverse effects on human and wildlife growth, development, and reproduction. It is therefore of primary importance to determine if drinking water could be contaminated by EDCs when produced from polluted surface waters. It is also essential to determine if disinfection by-products can account for estrogenic activity in treated waters.

Assessment of river contamination by estrogenic compounds in Paris area (France).

Wastewater treatment plants (WWTPs) receive a large spectrum of endocrine disrupting compounds (EDCs) that are partially eliminated during treatment processes and discharged into rivers. Given the lack of information in France about river contamination by EDCs, we chose to examine estrogenic potential of WWTP influents, effluents and receiving waters in Paris and its suburbs. Water samples were analyzed using gas chromatography coupled with mass spectrometry for quantifying natural and synthetic estrogens combined with an in vitro estrogenicity bioassay associated to a high pressure liquid chromatography fractionation.

UVA-induced cyclobutane pyrimidine dimers form predominantly at thymine-thymine dipyrimidines and correlate with the mutation spectrum in rodent cells.

Ligation-mediated PCR was employed to quantify cyclobutane pyrimidine dimer (CPD) formation at nucleotide resolution along exon 2 of the adenine phosphoribosyltransferase (aprt) locus in Chinese hamster ovary (CHO) cells following irradiation with either UVA (340-400 nm), UVB (295-320 nm), UVC (254 nm) or simulated sunlight (SSL; lambda > 295 nm). The resulting DNA damage spectrum for each wavelength region was then aligned with the corresponding mutational spectrum generated previously in the same genetic target. The DNA sequence specificities of CPD formation induced by UVC, UVB or SSL were very similar, i.