One of the features distinguishing SARS-CoV-2 from its more pathogenic counterpart SARS-CoV is the presence of premature stop codons in its ORF3b gene. Here, we show that SARS-CoV-2 ORF3b is a potent interferon antagonist, suppressing the induction of type I interferon more efficiently than its SARS-CoV ortholog. Phylogenetic analyses and functional assays reveal that SARS-CoV-2-related viruses from bats and pangolins also encode truncated ORF3b gene products with strong anti-interferon activity. Furthermore, analyses of approximately 17,000 SARS-CoV-2 sequences identify a natural variant in which a longer ORF3b reading frame was reconstituted. This variant was isolated from two patients with severe disease and further increased the ability of ORF3b to suppress interferon induction. Thus, our findings not only help to explain the poor interferon response in COVID-19 patients but also describe the emergence of natural SARS-CoV-2 quasispecies with an extended ORF3b gene that may potentially affect COVID-19 pathogenesis.
While human T-cell leukemia virus type 1 (HTLV-1) is associated with the development of adult T-cell leukemia (ATL), HTLV-2 has not been reported to be associated with such malignant leukemias. HTLV-1 Tax1 oncoprotein transforms a rat fibroblast cell line (Rat-1) to form multiple large colonies in soft agar, and this activity is much greater than that of HTLV-2 Tax2. We have demonstrated here that the increased number of transformed colonies induced by Tax1 relative to Tax2 was mediated by a PDZ domain-binding motif (PBM) in Tax1, which is absent in Tax2. Tax1 PBM mediated the interaction of Tax1 with the discs large (Dlg) tumor suppressor containing PDZ domains, and the interaction correlated well with the transforming activities of Tax1 and the mutants. Through this interaction, Tax1 altered the subcellular localization of Dlg from the detergent-soluble to the detergent-insoluble fraction in a fibroblast cell line as well as in HTLV-1-infected T-cell lines. These results suggest that the interaction of Tax1 with PDZ domain protein(s) is critically involved in the transforming activity of Tax1, the activity of which may be a crucial factor in malignant transformation of HTLV-1-infected cells in vivo.
Myelination is essential for proper functioning of the central nervous system (CNS). In this study, we have identified a mouse mutation, designated furue, which causes tremors and hypomyelination in the CNS, particularly in the spinal cord, but not in the sciatic nerve of the peripheral nervous system (PNS). In the spinal cord of the furue mice, myelination of small diameter axons was dramatically reduced and differentiation of oligodendrocytes, the myelin-forming cells in the CNS, was inhibited. We subsequently found that the furue mutation was associated with a transgene insertion into the teneurin-4 (Ten-4/Odz4) gene, encoding a transmembrane protein of unknown function. Ten-4 was strongly expressed in the spinal cord of wild-type mice and was induced during normal oligodendrocyte differentiation. In contrast, in the furue mice, the expression of Ten-4 was absent. Differentiation and cellular process formation of oligodendrocytes were inhibited in primary cell culture from the furue mice. Cell differentiation and process formation were also inhibited in the oligodendrocyte progenitor cell line CG-4 following suppression of Ten-4 expression by shRNA. Further, Ten-4 positively regulated focal adhesion kinase (FAK), an essential signaling molecule for oligodendrocyte process formation and myelination of small diameter axons. These findings suggest that Ten-4 is a novel regulator of oligodendrocyte differentiation and that it plays a critical role in the myelination of small diameter axons in the CNS.
Latency-associated nuclear antigen 1 (LANA1) of Kaposi's sarcoma-associated herpesvirus (KSHV; human herpesvirus 8) persistently maintains a plasmid containing the KSHV latent origin of replication (oriP) as a closed circular episome in dividing cells. In this study, we investigated the involvement of chromosome binding activity of LANA1 in persistent episome maintenance. Deletion of the N-terminal 22 amino acids of LANA1 (⌬N-LANA) inhibited the interaction with mitotic chromosomes in a human cell line, and the mutant concomitantly lost activity for the long-term episome maintenance of a plasmid containing viral oriP in a human B-cell line. However, a chimera of ⌬N-LANA with histone H1, a cellular chromosome component protein, rescued the association with mitotic chromosomes as well as the long-term episome maintenance of the oriP-containing plasmid. Our results suggest that tethering of KSHV episomes to mitotic chromosomes by LANA1 is crucial in mediating the long-term maintenance of viral episomes in dividing cells.Kaposi's sarcoma-associated herpesvirus (KSHV; human herpesvirus 8) is a gamma 2 herpesvirus and is associated with the development of Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease (5,6,10,17,21,24). KSHV can establish long-term persistent infections in tumor cells and lymphoma-derived cell lines. In such cells, the double-stranded KSHV DNA genome can persist as multiple copies of closed circular episomes (5, 9), like the genome of its close relative, Epstein-Barr virus (EBV).Two viral components can mediate the long-term episome maintenance of KSHV in infected cells. One is latency-associated nuclear antigen 1 (LANA1), encoded by open reading frame 73, and the other is a cis-acting DNA sequence (latent origin of replication [oriP]) in the 5Ј end of the KSHV genome (terminal repeat [TR] sequence) (1, 2, 7). LANA1 persistently maintains a plasmid containing multiple TRs as an episome in a human B-cell line (1, 2).Previous studies showed that LANA1 was directly bound to the KSHV TR sequence (2,8,11). Furthermore, an imperfect 20-bp palindrome in the TR sequence exhibited binding activity for LANA1, and a plasmid containing three TRs was persistently maintained as an episome in a human cell line (2, 11). Domain map analysis revealed that the C-terminal region of LANA1 bound to this 20-bp palindrome in the TR sequence (11). Since this region contains the LANA1 dimerization domain (22), it seems likely that LANA1 binds to the TR sequence as a dimer, like EBNA1, the episome maintenance protein of EBV.About 40 to 80 copies of episomes are stably maintained in KSHV-infected lymphoma cells in vivo (1, 4). The constant KSHV copy number in dividing cells indicates that KSHV has an efficient system for segregating viral episomes into two daughter cells in every cell division. In the present study, we examined the involvement of the chromosome interaction activity of LANA1 in long-term episome maintenance. A 22-amino-acid deletion from the N terminus of LANA1 (⌬N-LANA) inhibit...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.