Involvement of the p62/NRF2 signal transduction pathway on erythrophagocytosis

This deposit is composed by the main article plus the supplementary materials of the publication.Erythrophagocytosis, the phagocytic removal of damaged red blood cells (RBC), and subsequent phagolysosome biogenesis are important processes in iron/heme metabolism and homeostasis. Phagolysosome biogenesis implies the interaction of nascent phagosomes with endocytic compartments and also autophagy effectors. Here, we report that besides recruitment of microtubule-associated protein-1-light chain 3 (LC3), additional autophagy machinery such as sequestosome 1 (p62) is also acquired by single-membrane phagosomes at very early stages of the phagocytic process and that its acquisition is very important to the outcome of the process. In bone marrow-derived macrophages (BMDM) silenced for p62, RBC degradation is inhibited. P62, is also required for nuclear translocation and activation of the transcription factor Nuclear factor E2-related Factor 2 (NRF2) during erythrophagocytosis. Deletion of the Nrf2 allele reduces p62 expression and compromises RBC degradation. In conclusion, we reveal that erythrophagocytosis relies on an interplay between p62 and NRF2, potentially acting as protective mechanism to maintain reactive oxygen species at basal levels and preserve macrophage homeostasis.Fundação para a Ciência e a Tecnologia grants: (HMSP-ICT/0024/2010, UID/Multi/04462/2013, SFRH/BD/62197/2009, SFRH/BD/90258/2012, SFRH /BD/51877/2012, SFRH/BD/52293/2013, PTDC/SAU-TOX/116627/2010, HMSP-ICT/0022/2010 ); European Union FEDER support: (COMPETE, QREN, PT2020 Partnership Agreement), ERC grant: (ERC-2011-AdG 294709-DAMAGECONTROL).info:eu-repo/semantics/publishedVersio

MicroRNA silencing of tumor suppressor DLC-1 promotes efficient hepatitis C virus replication in primary human hepatocytes

MicroRNAs (miRNAs) are approximately 22-nucleotide noncoding RNAs that constitute silencers of target gene expression. Aberrant expression of miRNA has been linked to a variety of cancers, including hepatocellular carcinoma (HCC). Hepatitis C virus (HCV) infection is considered a major cause of chronic liver disease and HCC, although the mechanism of virus infection-associated hepatocarcinogenesis remains unclear. We report a direct role of miRNAs induced in HCV-infected primary human hepatocytes that target the tumor suppressor gene DLC-1 (a Rho GTPase-activating protein), which is frequently deleted in HCC, and other solid human tumors. MicroRNA miR-141 that targets DLC-1 was accentuated in cells infected with HCV genotypes 1a, 1b, and 2a. We present several lines of evidence that efficient HCV replication requires miR-141-mediated suppression of DLC-1. An increase in miR-141 correlated with the inhibition of DLC-1 protein in HCV-infected cells. Depletion of miR-141 with oligonucleotides complementary to the miRNAs inhibited virus replication, whereas artificially increased levels of intracellular miR-141 enhanced HCV replication. HCV-infected hepatocytes showed enhanced cell proliferation that can be countered by overexpression of DLC-1. Conclusion: The collective results of this study suggest a novel mechanism of HCV infection-associated miRNA-mediated regulation of a tumor suppressor protein that has the ability to influence cell proliferation and HCV infection-mediated liver cancer. © 2010 American Association for the Study of Liver Diseases.link_to_subscribed_fulltex