Amino acid deprivation triggers a novel GCN2-independent response leading to the transcriptional reactivation of non-native DNA sequences

• DOI: 10.1371/journal.pone.0200783
• Publication Date: 2018-07-18T19:27:58Z
• Authors: Annarosaria De Vito; Massimo Lazzaro; Ilaria Palmisano; Davide Cittaro; Michela Riba; Dejan Lazarevic; Makoto Bannai; Davide Gabellini; Maria Vittoria Sc...
• Keywords: Integrated stress response

In a variety of species, reduced food intake, and in particular protein or amino acid (AA) restriction, extends lifespan healthspan. However, the underlying epigenetic and/or transcriptional mechanisms are largely unknown, dissection specific pathways cultured cells may contribute to filling this gap. We have previously shown that, mammalian cells, deprivation essential AAs (methionine/cysteine tyrosine) leads reactivation integrated silenced transgenes, including plasmid retroviral vectors latent HIV-1 provirus, by process involving chromatic remodeling histone acetylation. Here we show that methionine/cysteine also upregulation endogenous retroviruses, suggesting AA starvation affects expression not only exogenous non-native DNA sequences, but anciently-integrated parasitic elements genome. Moreover, transgene response is highly conserved different cell types, it reproducible with most AAs. The General Control Non-derepressible 2 (GCN2) kinase downstream stress represent best candidates mediating process; however, pharmacological approaches, RNA interference genomic editing, demonstrate they implicated. Instead, requires MEK/ERK JNK activity reproduced ribosomal inhibitors, triggered novel nutrient-sensing signaling pathway, initiated translational block at ribosome, independent mTOR GCN2. Overall, these findings point general deprivation, which relevant implications for epigenetic/transcriptional effects restriction health disease.