Publications by authors named "Benedikt Agerer"

11 Publications

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The serine's call: Suppressing interferon responses.

Cell Metab 2021 May;33(5):849-850

CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. Electronic address:

Cellular metabolism and immune function are closely linked. In this issue of Cell Metabolism, Shen et al. (2021) identify serine metabolism as a central integration hub of cellular metabolism, antiviral immunity, and epigenetic regulation.
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http://dx.doi.org/10.1016/j.cmet.2021.04.012DOI Listing
May 2021

SARS-CoV-2 mutations in MHC-I-restricted epitopes evade CD8 T cell responses.

Sci Immunol 2021 03;6(57)

Department of Dermatology, Medical University of Vienna, Vienna, Austria.

CD8 T cell immunity to SARS-CoV-2 has been implicated in COVID-19 severity and virus control. Here, we identified nonsynonymous mutations in MHC-I-restricted CD8 T cell epitopes after deep sequencing of 747 SARS-CoV-2 virus isolates. Mutant peptides exhibited diminished or abrogated MHC-I binding in a cell-free in vitro assay. Reduced MHC-I binding of mutant peptides was associated with decreased proliferation, IFN-γ production and cytotoxic activity of CD8 T cells isolated from HLA-matched COVID-19 patients. Single cell RNA sequencing of ex vivo expanded, tetramer-sorted CD8 T cells from COVID-19 patients further revealed qualitative differences in the transcriptional response to mutant peptides. Our findings highlight the capacity of SARS-CoV-2 to subvert CD8 T cell surveillance through point mutations in MHC-I-restricted viral epitopes.
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http://dx.doi.org/10.1126/sciimmunol.abg6461DOI Listing
March 2021

Epistasis-driven identification of SLC25A51 as a regulator of human mitochondrial NAD import.

Nat Commun 2020 12 1;11(1):6145. Epub 2020 Dec 1.

CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.

About a thousand genes in the human genome encode for membrane transporters. Among these, several solute carrier proteins (SLCs), representing the largest group of transporters, are still orphan and lack functional characterization. We reasoned that assessing genetic interactions among SLCs may be an efficient way to obtain functional information allowing their deorphanization. Here we describe a network of strong genetic interactions indicating a contribution to mitochondrial respiration and redox metabolism for SLC25A51/MCART1, an uncharacterized member of the SLC25 family of transporters. Through a combination of metabolomics, genomics and genetics approaches, we demonstrate a role for SLC25A51 as enabler of mitochondrial import of NAD, showcasing the potential of genetic interaction-driven functional gene deorphanization.
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http://dx.doi.org/10.1038/s41467-020-19871-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708531PMC
December 2020

Genomic epidemiology of superspreading events in Austria reveals mutational dynamics and transmission properties of SARS-CoV-2.

Sci Transl Med 2020 12 23;12(573). Epub 2020 Nov 23.

Department of Theoretical Chemistry, University of Vienna, 1090 Vienna, Austria.

Superspreading events shaped the coronavirus disease 2019 (COVID-19) pandemic, and their rapid identification and containment are essential for disease control. Here, we provide a national-scale analysis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) superspreading during the first wave of infections in Austria, a country that played a major role in initial virus transmissions in Europe. Capitalizing on Austria's well-developed epidemiological surveillance system, we identified major SARS-CoV-2 clusters during the first wave of infections and performed deep whole-genome sequencing of more than 500 virus samples. Phylogenetic-epidemiological analysis enabled the reconstruction of superspreading events and charts a map of tourism-related viral spread originating from Austria in spring 2020. Moreover, we exploited epidemiologically well-defined clusters to quantify SARS-CoV-2 mutational dynamics, including the observation of low-frequency mutations that progressed to fixation within the infection chain. Time-resolved virus sequencing unveiled viral mutation dynamics within individuals with COVID-19, and epidemiologically validated infector-infectee pairs enabled us to determine an average transmission bottleneck size of 10 SARS-CoV-2 particles. In conclusion, this study illustrates the power of combining epidemiological analysis with deep viral genome sequencing to unravel the spread of SARS-CoV-2 and to gain fundamental insights into mutational dynamics and transmission properties.
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http://dx.doi.org/10.1126/scitranslmed.abe2555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857414PMC
December 2020

Hepatocyte-intrinsic type I interferon signaling reprograms metabolism and reveals a novel compensatory mechanism of the tryptophan-kynurenine pathway in viral hepatitis.

PLoS Pathog 2020 10 12;16(10):e1008973. Epub 2020 Oct 12.

CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse, Vienna, Austria.

The liver is a central regulator of metabolic homeostasis and serum metabolite levels. Hepatocytes are the functional units of the liver parenchyma and not only responsible for turnover of biomolecules but also act as central immune signaling platforms. Hepatotropic viruses infect liver tissue, resulting in inflammatory responses, tissue damage and hepatitis. Combining well-established in vitro and in vivo model systems with transcriptomic analyses, we show that type I interferon signaling initiates a robust antiviral immune response in hepatocytes. Strikingly, we also identify IFN-I as both, sufficient and necessary, to induce wide-spread metabolic reprogramming in hepatocytes. IFN-I specifically rewired tryptophan metabolism and induced hepatic tryptophan oxidation to kynurenine via Tdo2, correlating with altered concentrations of serum metabolites upon viral infection. Infected Tdo2-deficient animals displayed elevated serum levels of tryptophan and, unexpectedly, also vast increases in the downstream immune-suppressive metabolite kynurenine. Thus, Tdo2-deficiency did not result in altered serum homeostasis of the tryptophan to kynurenine ratio during infection, which seemed to be independent of hepatocyte-intrinsic compensation via the IDO-axis. These data highlight that inflammation-induced reprogramming of systemic tryptophan metabolism is tightly regulated in viral hepatitis.
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http://dx.doi.org/10.1371/journal.ppat.1008973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580883PMC
October 2020

Repression of the B cell identity factor Pax5 is not required for plasma cell development.

J Exp Med 2020 11;217(11)

Research Institute of Molecular Pathology, Vienna BioCenter, Vienna, Austria.

B cell and plasma cell fates are controlled by different transcriptional networks, as exemplified by the mutually exclusive expression and cross-antagonism of the B cell identity factor Pax5 and the plasma cell regulator Blimp1. It has been postulated that repression of Pax5 by Blimp1 is essential for plasma cell development. Here, we challenged this hypothesis by analyzing the IghPax5/+ mouse, which expressed a Pax5 minigene from the immunoglobulin heavy-chain locus. Despite high Pax5 expression, plasma cells efficiently developed in young IghPax5/+ mice at steady state and upon immunization, while their number moderately declined in older mice. Although Pax5 significantly deregulated the plasma cell expression program, key plasma cell regulators were normally expressed in IghPax5/+ plasma cells. While IgM and IgA secretion by IghPax5/+ plasma cells was normal, IgG secretion was modestly decreased. Hence, Pax5 repression is not essential for robust plasma cell development and antibody secretion, although it is required for optimal IgG production and accumulation of long-lived plasma cells.
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http://dx.doi.org/10.1084/jem.20200147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596824PMC
November 2020

Selective Mediator dependence of cell-type-specifying transcription.

Nat Genet 2020 07 1;52(7):719-727. Epub 2020 Jun 1.

CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.

The Mediator complex directs signals from DNA-binding transcription factors to RNA polymerase II (Pol II). Despite this pivotal position, mechanistic understanding of Mediator in human cells remains incomplete. Here we quantified Mediator-controlled Pol II kinetics by coupling rapid subunit degradation with orthogonal experimental readouts. In agreement with a model of condensate-driven transcription initiation, large clusters of hypophosphorylated Pol II rapidly disassembled upon Mediator degradation. This was accompanied by a selective and pronounced disruption of cell-type-specifying transcriptional circuits, whose constituent genes featured exceptionally high rates of Pol II turnover. Notably, the transcriptional output of most other genes was largely unaffected by acute Mediator ablation. Maintenance of transcriptional activity at these genes was linked to an unexpected CDK9-dependent compensatory feedback loop that elevated Pol II pause release rates across the genome. Collectively, our work positions human Mediator as a globally acting coactivator that selectively safeguards the functionality of cell-type-specifying transcriptional networks.
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http://dx.doi.org/10.1038/s41588-020-0635-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610447PMC
July 2020

Type I Interferon Signaling Disrupts the Hepatic Urea Cycle and Alters Systemic Metabolism to Suppress T Cell Function.

Immunity 2019 12 26;51(6):1074-1087.e9. Epub 2019 Nov 26.

CeMM Research Center for Molecular Medicine or the Austrian Academy of Sciences, Lazarettgasse 14 AKH BT25.3, 1090 Vienna, Austria. Electronic address:

Infections induce complex host responses linked to antiviral defense, inflammation, and tissue damage and repair. We hypothesized that the liver, as a central metabolic hub, may orchestrate systemic metabolic changes during infection. We infected mice with chronic lymphocytic choriomeningitis virus (LCMV), performed RNA sequencing and proteomics of liver tissue, and integrated these data with serum metabolomics at different infection phases. Widespread reprogramming of liver metabolism occurred early after infection, correlating with type I interferon (IFN-I) responses. Viral infection induced metabolic alterations of the liver that depended on the interferon alpha/beta receptor (IFNAR1). Hepatocyte-intrinsic IFNAR1 repressed the transcription of metabolic genes, including Otc and Ass1, which encode urea cycle enzymes. This led to decreased arginine and increased ornithine concentrations in the circulation, resulting in suppressed virus-specific CD8 T cell responses and ameliorated liver pathology. These findings establish IFN-I-induced modulation of hepatic metabolism and the urea cycle as an endogenous mechanism of immunoregulation. VIDEO ABSTRACT.
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http://dx.doi.org/10.1016/j.immuni.2019.10.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6926485PMC
December 2019

A repetitive acidic region contributes to the extremely rapid degradation of the cell-context essential protein TRIM52.

Sci Rep 2019 05 27;9(1):7901. Epub 2019 May 27.

Department of Microbiology, Immunobiology, and Genetics, Max F. Perutz Laboratories (MFPL), University of Vienna, Vienna Biocenter (VBC), Dr. Bohr-Gasse 9, 1030, Vienna, Austria.

Tripartite motif protein 52 (TRIM52) is a non-canonical TRIM family member harbouring the largest RING domain encoded in the human genome. In humans TRIM52 is conserved and has been under positive selection pressure, yet it has been lost in many non-primates. Competitive cell fitness assays demonstrated that TRIM52 ablation reduces cellular fitness in multiple different cell types. To better understand how this cell-essential factor is controlled, we investigated how expression of this non-canonical protein is regulated. Here, we show that TRIM52 mRNA is constitutively expressed from an intergenic region preceding the TRIM52 gene. Yet, TRIM52 protein is rapidly turned-over by the proteasome with a 3.5-minute half-life, one of the shortest in the human proteome. Consistent with this extremely rapid degradation rate, all three TRIM52 domains were identified to contribute to its instability. Intriguingly, a repetitive acidic loop in the RING domain was identified as one of the main destabilizing regions, which was unexpected given the prevailing notion that these sequences are poor proteasome substrates. This work indicates that the effect of such repetitive acidic regions on proteasomal degradation depends on the protein context, and it identifies TRIM52 as an attractive model protein to study what these contextual properties are.
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http://dx.doi.org/10.1038/s41598-019-44359-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536530PMC
May 2019

The ERBB-STAT3 Axis Drives Tasmanian Devil Facial Tumor Disease.

Cancer Cell 2019 01;35(1):125-139.e9

CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria. Electronic address:

The marsupial Tasmanian devil (Sarcophilus harrisii) faces extinction due to transmissible devil facial tumor disease (DFTD). To unveil the molecular underpinnings of this transmissible cancer, we combined pharmacological screens with an integrated systems-biology characterization. Sensitivity to inhibitors of ERBB tyrosine kinases correlated with their overexpression. Proteomic and DNA methylation analyses revealed tumor-specific signatures linked to the evolutionary conserved oncogenic STAT3. ERBB inhibition blocked phosphorylation of STAT3 and arrested cancer cells. Pharmacological blockade of ERBB or STAT3 prevented tumor growth in xenograft models and restored MHC class I expression. This link between the hyperactive ERBB-STAT3 axis and major histocompatibility complex class I-mediated tumor immunosurveillance provides mechanistic insights into horizontal transmissibility and puts forward a dual chemo-immunotherapeutic strategy to save Tasmanian devils from DFTD. VIDEO ABSTRACT.
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http://dx.doi.org/10.1016/j.ccell.2018.11.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335503PMC
January 2019

Human tripartite motif protein 52 is required for cell context-dependent proliferation.

Oncotarget 2018 Mar 5;9(17):13565-13581. Epub 2018 Feb 5.

Department of Microbiology, Immunobiology, and Genetics, Max F. Perutz Laboratories, University of Vienna, Vienna Biocenter, Vienna 1030, Austria.

Tripartite motif (TRIM) proteins have been shown to play important roles in cancer development and progression by modulating cell proliferation or resistance from cell death during non-homeostatic stress conditions found in tumor micro-environments. In this study, we set out to investigate the importance for cellular fitness of the virtually uncharacterized family member TRIM52. The human gene has arisen recently in evolution, making it unlikely that TRIM52 is required for basic cellular functions in normal cells. However, a recent genome-wide ablation screening study has suggested that TRIM52 may be essential for optimal proliferation or survival in certain genetic cancer backgrounds. Identifying genes which fit this concept of genetic context-dependent fitness in cancer cells is of interest as they are promising targets for tumor-specific therapy. We report here that ablation significantly diminished the proliferation of specific glioblastoma cell lines in cell culture and mouse xenografts by compromising their cell cycle progression in a p53-dependent manner. Together, our findings point to a non-redundant TRIM52 function that is required for optimal proliferation.
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http://dx.doi.org/10.18632/oncotarget.24422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5862599PMC
March 2018