The Epigenetic Controller Lysine-Specific Demethylase 1 (LSD1) Regulates the Outcome of Hepatitis C Viral Infection.

Hepatitis C virus (HCV) alters gene expression epigenetically to rearrange the cellular microenvironment in a beneficial way for its life cycle. The host epigenetic changes induced by HCV lead to metabolic dysfunction and malignant transformation. Lysine-specific demethylase 1 (LSD1) is an epigenetic controller of critical cellular functions that are essential for HCV propagation. We investigated the putative role of LSD1 in the establishment of HCV infection using genetic engineering and pharmacological inhibition to alter endogenous LSD1 levels. We demonstrated for the first time that HCV replication was inhibited in LSD1-overexpressing cells, while specific HCV proteins differentially fine-tuned endogenous LSD1 expression levels. Electroporation of the full-length HCV genome and subgenomic replicons in LSD1 overexpression enhanced translation and partially restored HCV replication, suggesting that HCV might be inhibited by LSD1 during the early steps of infection. Conversely, the inhibition of LSD1, followed by HCV infection in vitro, increased viral replication. LSD1 was shown to participate in an intriguing antiviral mechanism, where it activates endolysosomal interferon-induced transmembrane protein 3 (IFITM3) via demethylation, leading endocytosed HCV virions to degradation. Our study proposes that HCV-mediated LSD1 oscillations over countless viral life cycles throughout chronic HCV infection may promote epigenetic changes related to HCV-induced hepatocarcinogenesis.

Proteomic Identification of the SLC25A46 Interactome in Transgenic Mice Expressing SLC25A46-FLAG.

The outer mitochondrial membrane protein SLC25A46 has been recently identified as a novel genetic cause of a wide spectrum of neurological diseases. The aim of the present work was to elucidate the physiological role of SLC25A46 through the identification of its interactome with immunoprecipitation and proteomic analysis in whole cell extracts from the cerebellum, cerebrum, heart, and thymus of transgenic mice expressing ubiquitously SLC25A46-FLAG. Our analysis identified 371 novel putative interactors of SLC25A46 and confirmed 17 known ones. A total of 79 co-immunoprecipitated proteins were common in two or more tissues, mainly participating in mitochondrial activities such as oxidative phosphorylation (OXPHOS) and ATP production, active transport of ions or molecules, and the metabolism. Tissue-specific co-immunoprecipitated proteins were enriched for synapse annotated proteins in the cerebellum and cerebrum for metabolic processes in the heart and for nuclear processes and proteasome in the thymus. Our proteomic approach confirmed known mitochondrial interactors of SLC25A46 including MICOS complex subunits and also OPA1 and VDACs, while we identified novel interactors including the ADP/ATP translocases SLC25A4 and SLC25A5, subunits of the OXPHOS complexes and F1Fo-ATP synthase, and components of the mitochondria-ER contact sites. Our results show that SLC25A46 interacts with a large number of proteins and protein complexes involved in the mitochondria architecture, energy production, and flux and also in inter-organellar contacts.