TY  - INPR
A1  - Hennig, Thomas
A1  - Prusty, Archana B.
A1  - Kaufer, Benedikt
A1  - Whisnant, Adam W.
A1  - Lodha, Manivel
A1  - Enders, Antje
A1  - Thomas, Julius
A1  - Kasimir, Francesca
A1  - Grothey, Arnhild
A1  - Herb, Stefanie
A1  - Jürges, Christopher
A1  - Meister, Gunter
A1  - Erhard, Florian
A1  - Dölken, Lars
A1  - Prusty, Bhupesh K.
T1  - Selective inhibition of microRNA processing by a herpesvirus-encoded microRNA triggers virus reactivation from latency
N2  - Herpesviruses have mastered host cell modulation and immune evasion to augment productive infection, life-long latency and reactivation thereof 1,2. A long appreciated, yet elusively defined relationship exists between the lytic-latent switch and viral non-coding RNAs 3,4. Here, we identify miRNA-mediated inhibition of miRNA processing as a novel cellular mechanism that human herpesvirus 6A (HHV-6A) exploits to disrupt mitochondrial architecture, evade intrinsic host defense and drive the latent-lytic switch. We demonstrate that virus-encoded miR-aU14 selectively inhibits the processing of multiple miR-30 family members by direct interaction with the respective pri-miRNA hairpin loops. Subsequent loss of miR-30 and activation of miR-30/p53/Drp1 axis triggers a profound disruption of mitochondrial architecture, which impairs induction of type I interferons and is necessary for both productive infection and virus reactivation. Ectopic expression of miR-aU14 was sufficient to trigger virus reactivation from latency thereby identifying it as a readily drugable master regulator of the herpesvirus latent-lytic switch. Our results show that miRNA-mediated inhibition of miRNA processing represents a generalized cellular mechanism that can be exploited to selectively target individual members of miRNA families. We anticipate that targeting miR-aU14 provides exciting therapeutic options for preventing herpesvirus reactivations in HHV-6-associated disorders like myalgic encephalitis/chronic fatigue syndrome (ME/CFS) and Long-COVID.
KW  - Herpesvirus
KW  - HHV-6
KW  - miRNA processing
KW  - miR-30
KW  - mitochondria
KW  - fusion and fission
KW  - type I interferon
KW  - latency
KW  - virus reactivation
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-267858
UR  - https://doi.org/10.21203/rs.3.rs-820696/v1
ET  - submitted version
ER  - 
TY  - JOUR
A1  - Whisnant, Adam W.
A1  - Jürges, Christopher S.
A1  - Hennig, Thomas
A1  - Wyler, Emanuel
A1  - Prusty, Bhupesh
A1  - Rutkowski, Andrzej J.
A1  - L'hernault, Anne
A1  - Djakovic, Lara
A1  - Göbel, Margarete
A1  - Döring, Kristina
A1  - Menegatti, Jennifer
A1  - Antrobus, Robin
A1  - Matheson, Nicholas J.
A1  - Künzig, Florian W. H.
A1  - Mastrobuoni, Guido
A1  - Bielow, Chris
A1  - Kempa, Stefan
A1  - Liang, Chunguang
A1  - Dandekar, Thomas
A1  - Zimmer, Ralf
A1  - Landthaler, Markus
A1  - Grässer, Friedrich
A1  - Lehner, Paul J.
A1  - Friedel, Caroline C.
A1  - Erhard, Florian
A1  - Dölken, Lars
T1  - Integrative functional genomics decodes herpes simplex virus 1
JF  - Nature Communications
N2  - The predicted 80 open reading frames (ORFs) of herpes simplex virus 1 (HSV-1) have been intensively studied for decades. Here, we unravel the complete viral transcriptome and translatome during lytic infection with base-pair resolution by computational integration of multi-omics data. We identify a total of 201 transcripts and 284 ORFs including all known and 46 novel large ORFs. This includes a so far unknown ORF in the locus deleted in the FDA-approved oncolytic virus Imlygic. Multiple transcript isoforms expressed from individual gene loci explain translation of the vast majority of ORFs as well as N-terminal extensions (NTEs) and truncations. We show that NTEs with non-canonical start codons govern the subcellular protein localization and packaging of key viral regulators and structural proteins. We extend the current nomenclature to include all viral gene products and provide a genome browser that visualizes all the obtained data from whole genome to single-nucleotide resolution. Here, using computational integration of multi-omics data, the authors provide a detailed transcriptome and translatome of herpes simplex virus 1 (HSV-1), including previously unidentified ORFs and N-terminal extensions. The study also provides a HSV-1 genome browser and should be a valuable resource for further research.
KW  - infected-cell protein
KW  - messenger RNA
KW  - binding protein
KW  - type 1
KW  - identification
KW  - ICP27
KW  - translation
KW  - expression
KW  - sequence
KW  - domain
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229884
VL  - 11
ER  - 
TY  - JOUR
A1  - Lodha, Manivel
A1  - Muchsin, Ihsan
A1  - Jürges, Christopher
A1  - Juranic Lisnic, Vanda
A1  - L’Hernault, Anne
A1  - Rutkowski, Andrzej J.
A1  - Prusty, Bhupesh K.
A1  - Grothey, Arnhild
A1  - Milic, Andrea
A1  - Hennig, Thomas
A1  - Jonjic, Stipan
A1  - Friedel, Caroline C.
A1  - Erhard, Florian
A1  - Dölken, Lars
T1  - Decoding murine cytomegalovirus
JF  - PLOS Pathogens
N2  - The genomes of both human cytomegalovirus (HCMV) and murine cytomegalovirus (MCMV) were first sequenced over 20 years ago. Similar to HCMV, the MCMV genome had initially been proposed to harbor ≈170 open reading frames (ORFs). More recently, omics approaches revealed HCMV gene expression to be substantially more complex comprising several hundred viral ORFs. Here, we provide a state-of-the art reannotation of lytic MCMV gene expression based on integrative analysis of a large set of omics data. Our data reveal 365 viral transcription start sites (TiSS) that give rise to 380 and 454 viral transcripts and ORFs, respectively. The latter include 200 small ORFs, some of which represented the most highly expressed viral gene products. By combining TiSS profiling with metabolic RNA labelling and chemical nucleotide conversion sequencing (dSLAM-seq), we provide a detailed picture of the expression kinetics of viral transcription. This not only resulted in the identification of a novel MCMV immediate early transcript encoding the m166.5 ORF, which we termed ie4, but also revealed a group of well-expressed viral transcripts that are induced later than canonical true late genes and contain an initiator element (Inr) but no TATA- or TATT-box in their core promoters. We show that viral upstream ORFs (uORFs) tune gene expression of longer viral ORFs expressed in cis at translational level. Finally, we identify a truncated isoform of the viral NK-cell immune evasin m145 arising from a viral TiSS downstream of the canonical m145 mRNA. Despite being ≈5-fold more abundantly expressed than the canonical m145 protein it was not required for downregulating the NK cell ligand, MULT-I. In summary, our work will pave the way for future mechanistic studies on previously unknown cytomegalovirus gene products in an important virus animal model.
KW  - virology
KW  - genetics
KW  - molecular biology
KW  - immunology
KW  - microbiology
KW  - parasitology
KW  - murine cytomegalovirus (MCMV)
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-350480
SN  - 1553-7374
VL  - 19
IS  - 5
ER  -