TY  - JOUR
A1  - Lodha, Manivel
A1  - Erhard, Florian
A1  - Dölken, Lars
A1  - Prusty, Bhupesh K.
T1  - The hidden enemy within: non-canonical peptides in virus-induced autoimmunity
JF  - Frontiers in Microbiology
N2  - Viruses play a key role in explaining the pathogenesis of various autoimmune disorders, whose underlying principle is defined by the activation of autoreactive T-cells. In many cases, T-cells escape self-tolerance due to the failure in encountering certain MHC-I self-peptide complexes at substantial levels, whose peptides remain invisible from the immune system. Over the years, contribution of unstable defective ribosomal products (DRiPs) in immunosurveillance has gained prominence. A class of unstable products emerge from non-canonical translation and processing of unannotated mammalian and viral ORFs and their peptides are cryptic in nature. Indeed, high throughput sequencing and proteomics have revealed that a substantial portion of our genomes comprise of non-canonical ORFs, whose generation is significantly modulated during disease. Many of these ORFs comprise short ORFs (sORFs) and upstream ORFs (uORFs) that resemble DRiPs and may hence be preferentially presented. Here, we discuss how such products, normally “hidden” from the immune system, become abundant in viral infections activating autoimmune T-cells, by discussing their emerging role in infection and disease. Finally, we provide a perspective on how these mechanisms can explain several autoimmune disorders in the wake of the COVID-19 pandemic.
KW  - viruses
KW  - cryptic peptides
KW  - autoimmunity
KW  - defective ribosomal products
KW  - non-canonical translation
KW  - COVID-19
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-263053
SN  - 1664-302X
VL  - 13
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  -