Refine
Has Fulltext
- yes (22) (remove)
Is part of the Bibliography
- yes (22)
Year of publication
Document Type
- Journal article (20)
- Preprint (2)
Language
- English (22)
Keywords
- COVID-19 (2)
- Herpesvirus (2)
- RNA polymerase II (2)
- SARS-CoV-2 (2)
- autoimmunity (2)
- binding protein (2)
- fusion and fission (2)
- gene expression (2)
- herpes simplex virus (2)
- identification (2)
Institute
- Institut für Virologie und Immunbiologie (22)
- Theodor-Boveri-Institut für Biowissenschaften (4)
- Lehrstuhl für Biochemie (2)
- Medizinische Klinik und Poliklinik II (2)
- Frauenklinik und Poliklinik (1)
- Institut für Anatomie und Zellbiologie (1)
- Institut für Hygiene und Mikrobiologie (1)
- Institut für Mathematik (1)
- Institut für diagnostische und interventionelle Neuroradiologie (ehem. Abteilung für Neuroradiologie) (1)
- Klinik und Poliklinik für Anästhesiologie (ab 2004) (1)
EU-Project number / Contract (GA) number
- 721016 (4)
- 101041177 (1)
- 677673 (1)
- 955974 (1)
- CoG 721016–HERPES (1)
- ERC-2016-CoG 721016-HERPES (1)
In invertebrates, small interfering RNAs are at the vanguard of cell-autonomous antiviral immunity. In contrast, antiviral mechanisms initiated by interferon (IFN) signaling predominate in mammals. Whilst mammalian IFN-induced miRNA are known to inhibit specific viruses, it is not known whether host-directed microRNAs, downstream of IFN-signaling, have a role in mediating broad antiviral resistance. By performing an integrative, systematic, global analysis of RNA turnover utilizing 4-thiouridine labeling of newly transcribed RNA and pri/pre-miRNA in IFN-activated macrophages, we identify a new post-transcriptional viral defense mechanism mediated by miR-342-5p. On the basis of ChIP and site-directed promoter mutagenesis experiments, we find the synthesis of miR-342-5p is coupled to the antiviral IFN response via the IFN-induced transcription factor, IRF1. Strikingly, we find miR-342-5p targets mevalonate-sterol biosynthesis using a multihit mechanism suppressing the pathway at different functional levels: transcriptionally via SREBF2, post-transcriptionally via miR-33, and enzymatically via IDI1 and SC4MOL. Mass spectrometry-based lipidomics and enzymatic assays demonstrate the targeting mechanisms reduce intermediate sterol pathway metabolites and total cholesterol in macrophages. These results reveal a previously unrecognized mechanism by which IFN regulates the sterol pathway. The sterol pathway is known to be an integral part of the macrophage IFN antiviral response, and we show that miR-342-5p exerts broad antiviral effects against multiple, unrelated pathogenic viruses such Cytomegalovirus and Influenza A (H1N1). Metabolic rescue experiments confirm the specificity of these effects and demonstrate that unrelated viruses have differential mevalonate and sterol pathway requirements for their replication. This study, therefore, advances the general concept of broad antiviral defense through multihit targeting of a single host pathway.
A Review of the Multipronged Attack of Herpes Simplex Virus 1 on the Host Transcriptional Machinery
(2021)
During lytic infection, herpes simplex virus (HSV) 1 induces a rapid shutoff of host RNA synthesis while redirecting transcriptional machinery to viral genes. In addition to being a major human pathogen, there is burgeoning clinical interest in HSV as a vector in gene delivery and oncolytic therapies, necessitating research into transcriptional control. This review summarizes the array of impacts that HSV has on RNA Polymerase (Pol) II, which transcribes all mRNA in infected cells. We discuss alterations in Pol II holoenzymes, post-translational modifications, and how viral proteins regulate specific activities such as promoter-proximal pausing, splicing, histone repositioning, and termination with respect to host genes. Recent technological innovations that have reshaped our understanding of previous observations are summarized in detail, along with specific research directions and technical considerations for future studies.