The interferon-inducible isoform of NCOA7 inhibits endosome-mediated viral entry

Abstract

Interferons (IFNs) mediate cellular defence against viral pathogens by upregulation of interferon-stimulated genes (ISGs) whose products interact with viral components or alter cellular physiology to suppress viral replication ( 1 – 3 ). Among the ISGs that can inhibit influenza A virus (IAV) ( 4 ) are the myxovirus resistance 1 (MX1) GTPase ( 5 ) and IFN-induced transmembrane protein 3 (IFITM3) ( 6 , 7 ). Here we use ectopic expression and gene knock-out to demonstrate that the IFN-inducible 219 amino acid short isoform of human nuclear receptor coactivator 7 (NCOA7) is an inhibitor of IAV as well as other viruses that enter the cell by endocytosis, including hepatitis C virus (HCV). NCOA7 interacts with the vacuolar H + -ATPase (V-ATPase) and its expression promotes cytoplasmic vesicle acidification, lysosomal protease activity and the degradation of endocytosed antigen. Step-wise dissection of the IAV entry pathway demonstrates that NCOA7 inhibits fusion of the viral and endosomal membranes and subsequent nuclear translocation of viral ribonucleoproteins (vRNPs). NCOA7, therefore, provides a mechanism for immune regulation of endo-lysosomal physiology that not only suppresses viral entry into the cytosol from this compartment but may also regulate other V-ATPase-associated cellular processes such as physiological adjustments to nutritional status, or the maturation and function of antigen presenting cells.

ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease

“…Loss of OXR1 results in pronounced microgliosis whilst neuronal OXR1 overexpression delays inflammation, indicating OXR1 regulation of microglial activation in a non-cell-autonomous fashion [ 184 ]. Finally, a unique, short-isoform of NCOA7, NCOA7-B or NCOA7-AS, is strongly linked to inflammatory activation, especially by viral-related stimuli such as interferons (IFNs), and functional inhibition of endosome-mediated viral-entry by NCOA7-B has been demonstrated [ 185 ]. Furthermore, NCOA7 is induced in epithelial cells in response to rhinovirus infection and LPS-stimulated macrophages, the peripheral myeloid cousins of microglia [ 186 , 187 ].…”

GILT restricts the cellular entry mediated by the envelope glycoproteins of SARS-CoV, Ebola virus and Lassa fever virus

“…Many ISGs are cellintrinsic restriction factors that are constitutively expressed in barrier cells such as epithelial cells, endothelial cells and macrophages and restrain viral infection by directly targeting various stages of virus life cycle [7]. So far, several ISGs, including interferoninduced transmembrane proteins (IFITM), cholesterol-25-hydroxylase (CH25H), ArfGAP with dual pleckstrin homology domains 2 (ADAP2) and a short isoform of nuclear receptor coactivator 7 (NCOA7) have been identified to block the viral entry by inhibiting virus-host cell membrane fusion or endocytic trafficking of internalized virions [8][9][10][11][12][13]. Some other ISGs target post-entry steps of viral life cycle, as exemplified by TRIM5α and Mx that block the nucleocapsid uncoating, RNase L and ISG20 that degrade viral RNA, PKR that inhibits viral protein translation, BST2 and Viperin that inhibit virion assembly or budding (reviewed in [7]).…”

Consensus transcriptional regulatory networks of coronavirus-infected human cells

“…This is consistent with previous reports of an appreciable divergence between IAV and SARS2 infection with respect to the interferon transcriptional response 8 . Other genes with known critical roles in the response to viral infection have high rankings in the CoV consensomes, including NCOA7 14 (percentiles: SARS1, 98 th ; SARS2, 97 th ; MERS, 89 th ; IAV, 99 th ), STAT1 15 (percentiles: SARS1, 99 th ; SARS2, 98 th ; MERS, 89 th ; IAV, 99 th ) and TAP1 16 (percentiles: SARS1, 99 th ; SARS2, 94 th ; MERS, 83 rd ; IAV, 99 th ). In addition to the appropriate elevated rankings for these known viral response effectors, the CoV consensomes assign similarly elevated rankings to transcripts that are largely or completely uncharacterized in the context of viral infection.…”