Publications by authors named "Ulrich Goldmann"

9 Publications

  • Page 1 of 1

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-19871-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708531PMC
December 2020

A substrate-based ontology for human solute carriers.

Mol Syst Biol 2020 07;16(7):e9652

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

Solute carriers (SLCs) are the largest family of transmembrane transporters in the human genome with more than 400 members. Despite the fact that SLCs mediate critical biological functions and several are important pharmacological targets, a large proportion of them is poorly characterized and present no assigned substrate. A major limitation to systems-level de-orphanization campaigns is the absence of a structured, language-controlled chemical annotation. Here we describe a thorough manual annotation of SLCs based on literature. The annotation of substrates, transport mechanism, coupled ions, and subcellular localization for 446 human SLCs confirmed that ~30% of these were still functionally orphan and lacked known substrates. Application of a substrate-based ontology to transcriptomic datasets identified SLC-specific responses to external perturbations, while a machine-learning approach based on the annotation allowed us to identify potential substrates for several orphan SLCs. The annotation is available at https://opendata.cemm.at/gsflab/slcontology/. Given the increasing availability of large biological datasets and the growing interest in transporters, we expect that the effort presented here will be critical to provide novel insights into the functions of SLCs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.15252/msb.20209652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7374931PMC
July 2020

TASL is the SLC15A4-associated adaptor for IRF5 activation by TLR7-9.

Nature 2020 05 13;581(7808):316-322. Epub 2020 May 13.

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

Toll-like receptors (TLRs) have a crucial role in the recognition of pathogens and initiation of immune responses. Here we show that a previously uncharacterized protein encoded by CXorf21-a gene that is associated with systemic lupus erythematosus-interacts with the endolysosomal transporter SLC15A4, an essential but poorly understood component of the endolysosomal TLR machinery also linked to autoimmune disease. Loss of this type-I-interferon-inducible protein, which we refer to as 'TLR adaptor interacting with SLC15A4 on the lysosome' (TASL), abrogated responses to endolysosomal TLR agonists in both primary and transformed human immune cells. Deletion of SLC15A4 or TASL specifically impaired the activation of the IRF pathway without affecting NF-κB and MAPK signalling, which indicates that ligand recognition and TLR engagement in the endolysosome occurred normally. Extensive mutagenesis of TASL demonstrated that its localization and function relies on the interaction with SLC15A4. TASL contains a conserved pLxIS motif (in which p denotes a hydrophilic residue and x denotes any residue) that mediates the recruitment and activation of IRF5. This finding shows that TASL is an innate immune adaptor for TLR7, TLR8 and TLR9 signalling, revealing a clear mechanistic analogy with the IRF3 adaptors STING, MAVS and TRIF. The identification of TASL as the component that links endolysosomal TLRs to the IRF5 transcription factor via SLC15A4 provides a mechanistic explanation for the involvement of these proteins in systemic lupus erythematosus.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-020-2282-0DOI Listing
May 2020

The RESOLUTE consortium: unlocking SLC transporters for drug discovery.

Authors:
Giulio Superti-Furga Daniel Lackner Tabea Wiedmer Alvaro Ingles-Prieto Barbara Barbosa Enrico Girardi Ulrich Goldmann Bettina Gürtl Kristaps Klavins Christoph Klimek Sabrina Lindinger Eva Liñeiro-Retes André C Müller Svenja Onstein Gregor Redinger Daniela Reil Vitaly Sedlyarov Gernot Wolf Matthew Crawford Robert Everley David Hepworth Shenping Liu Stephen Noell Mary Piotrowski Robert Stanton Hui Zhang Salvatore Corallino Andrea Faedo Maria Insidioso Giovanna Maresca Loredana Redaelli Francesca Sassone Lia Scarabottolo Michela Stucchi Paola Tarroni Sara Tremolada Helena Batoulis Andreas Becker Eckhard Bender Yung-Ning Chang Alexander Ehrmann Anke Müller-Fahrnow Vera Pütter Diana Zindel Bradford Hamilton Martin Lenter Diana Santacruz Coralie Viollet Charles Whitehurst Kai Johnsson Philipp Leippe Birgit Baumgarten Lena Chang Yvonne Ibig Martin Pfeifer Jürgen Reinhardt Julian Schönbett Paul Selzer Klaus Seuwen Charles Bettembourg Bruno Biton Jörg Czech Hélène de Foucauld Michel Didier Thomas Licher Vincent Mikol Antje Pommereau Frédéric Puech Veeranagouda Yaligara Aled Edwards Brandon J Bongers Laura H Heitman Ad P IJzerman Huub J Sijben Gerard J P van Westen Justine Grixti Douglas B Kell Farah Mughal Neil Swainston Marina Wright-Muelas Tina Bohstedt Nicola Burgess-Brown Liz Carpenter Katharina Dürr Jesper Hansen Andreea Scacioc Giulia Banci Claire Colas Daniela Digles Gerhard Ecker Barbara Füzi Viktoria Gamsjäger Melanie Grandits Riccardo Martini Florentina Troger Patrick Altermatt Cédric Doucerain Franz Dürrenberger Vania Manolova Anna-Lena Steck Hanna Sundström Maria Wilhelm Claire M Steppan

Nat Rev Drug Discov 2020 07;19(7):429-430

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/d41573-020-00056-6DOI Listing
July 2020

A 2-year longitudinal study of neuropsychological functioning, psychosocial adjustment and rehospitalisation in schizophrenia and major depression.

Eur Arch Psychiatry Clin Neurosci 2020 Sep 3;270(6):699-708. Epub 2020 Apr 3.

Department of Psychiatry and Psychotherapy, University Hospital, Ludwig Maximilian University of Munich, Nussbaumstr.7, 80336, Munich, Germany.

Neuropsychological functioning turns out to be a rate-limiting factor in psychiatry. However, little is known when comparing neuropsychological and psychosocial functioning in inpatients with schizophrenia or severe depression in their treatment pathways including add-on psychoeducation or the latter combined with cognitive behavioral therapy up to 2-year follow-up. To evaluate this question, we investigated these variables in two randomised controlled trials including 196 patients with DSM-IV schizophrenia and 177 patients with major depression. Outcome measures were assessed in the hospital at pre- and posttreatment and following discharge until 2-year follow-up. We focused on neuropsychological and psychosocial functioning regarding its differences and changes over time in data of two pooled trials. There were significant time effects indicating gains in knowledge about the illness, short and medium-term memory (VLMT) and psychosocial functioning (GAF), however, the latter was the only variable showing a time x study/diagnosis interaction effect at 2-year follow-up, showing significant better outcome in depression compared to schizophrenia. Moderator analysis showed no changes in psychosocial and neuropsychological functioning in schizophrenia and in affective disorders due to age, duration of illness or sex. Looking at the rehospitalisation rates there were no significant differences between both disorders. Both groups treated with psychoeducation or a combination of psychoeducation and CBT improved in neuropsychological and psychosocial functioning as well as knowledge about the illness at 2-year follow-up, however, patients with major depression showed greater gains in psychosocial functioning compared to patients with schizophrenia. Possible implications of these findings were discussed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00406-020-01118-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423783PMC
September 2020

The transporters SLC35A1 and SLC30A1 play opposite roles in cell survival upon VSV virus infection.

Sci Rep 2019 07 18;9(1):10471. Epub 2019 Jul 18.

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

Host factor requirements for different classes of viruses have not been fully unraveled. Replication of the viral genome and synthesis of viral proteins within the human host cell are associated with an increased demand for nutrients and specific metabolites. With more than 400 acknowledged members to date in humans, solute carriers (SLCs) represent the largest family of transmembrane proteins dedicated to the transport of ions and small molecules such as amino acids, sugars and nucleotides. Consistent with their impact on cellular metabolism, several SLCs have been implicated as host factors affecting the viral life cycle and the cellular response to infection. In this study, we aimed at characterizing the role of host SLCs in cell survival upon viral infection by performing unbiased genetic screens using a focused CRISPR knockout library. Genetic screens with the cytolytic vesicular stomatitis virus (VSV) showed that the loss of two SLCs genes, encoding the sialic acid transporter SLC35A1/CST and the zinc transporter SLC30A1/ZnT1, affected cell survival upon infection. Further characterization of these genes suggests a role for both of these transporters in the apoptotic response induced by VSV, offering new insights into the cellular response to oncolytic virus infections.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-46952-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639343PMC
July 2019

The in silico human surfaceome.

Proc Natl Acad Sci U S A 2018 11 29;115(46):E10988-E10997. Epub 2018 Oct 29.

Institute of Molecular Systems Biology at the Department of Biology, ETH Zurich, 8093 Zurich, Switzerland;

Cell-surface proteins are of great biomedical importance, as demonstrated by the fact that 66% of approved human drugs listed in the DrugBank database target a cell-surface protein. Despite this biomedical relevance, there has been no comprehensive assessment of the human surfaceome, and only a fraction of the predicted 5,000 human transmembrane proteins have been shown to be located at the plasma membrane. To enable analysis of the human surfaceome, we developed the surfaceome predictor SURFY, based on machine learning. As a training set, we used experimentally verified high-confidence cell-surface proteins from the Cell Surface Protein Atlas (CSPA) and trained a random forest classifier on 131 features per protein and, specifically, per topological domain. SURFY was used to predict a human surfaceome of 2,886 proteins with an accuracy of 93.5%, which shows excellent overlap with known cell-surface protein classes (i.e., receptors). In deposited mRNA data, we found that between 543 and 1,100 surfaceome genes were expressed in cancer cell lines and maximally 1,700 surfaceome genes were expressed in embryonic stem cells and derivative lines. Thus, the surfaceome diversity depends on cell type and appears to be more dynamic than the nonsurface proteome. To make the predicted surfaceome readily accessible to the research community, we provide visualization tools for intuitive interrogation (wlab.ethz.ch/surfaceome). The in silico surfaceome enables the filtering of data generated by multiomics screens and supports the elucidation of the surfaceome nanoscale organization.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1808790115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6243280PMC
November 2018

Efficacy of extended clinical management, group CBT, and group plus individual CBT for major depression: Results of a two-year follow-up study.

J Affect Disord 2018 10 13;238:570-578. Epub 2018 Jun 13.

Professor of Psychiatry emeritus, M.D., Department of Psychiatry and Psychotherapy, University of Munich, Munich D-80336, Germany. Electronic address:

Objective: Cognitive therapy has gained prominence in the treatment of major depression, however, little is known about its long-term benefits when delivered during inpatient treatment or combined with outpatient treatment with severely ill inpatients (HAM-D > 20).

Method: To evaluate this question, we conducted a randomized controlled trial investigating the efficacy of extended clinical management (E-CM), psychoeducational cognitive behavioural group therapy (PCBT-G) or PCBT-G and 16 outpatient individual treatment sessions (PCBT-G+I). All patients were treated with pharmacotherapy. 177 inpatients with DSM-IV major depression were randomized either to E-CM or PCBT-G or PCBT-G+I. Outcome measures were collected in the hospital at pre- and posttreatment and following discharge into the community every six months for two years. We compared the study groups on symptom changes, psychosocial functioning, knowledge about depression and rehospitalization.

Results: All three treatment interventions are equally effective at reducing depressive symptoms and increasing psychosocial functioning at posttreatment. There was significant group by time interaction for knowledge about depression in favor of PCBT-G and PCBT-G+I over E-CM. We did not find significantly lower rehospitalisation rates at the two-year follow-up for PCBT-G+I compared to E-CM, however, comparing PCBT-G to E-CM.

Conclusions: We conclude that with cognitive psychoeducational group therapy a successful, in the long-term other interventions superior psychological intervention for major depression is available as gains were sustained for two years following discharge from the hospital. More research is needed to evaluate the long-term impact of group treatment starting in inpatient treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jad.2018.05.081DOI Listing
October 2018

The Bicarbonate Transporter SLC4A7 Plays a Key Role in Macrophage Phagosome Acidification.

Cell Host Microbe 2018 06 17;23(6):766-774.e5. Epub 2018 May 17.

CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria; Center for Physiology and Pharmacology, Medical University of Vienna, Vienna 1090, Austria. Electronic address:

Macrophages represent the first line of immune defense against pathogens, and phagosome acidification is a necessary step in pathogen clearance. Here, we identified the bicarbonate transporter SLC4A7, which is strongly induced upon macrophage differentiation, as critical for phagosome acidification. Loss of SLC4A7 reduced acidification of phagocytosed beads or bacteria and impaired the intracellular microbicidal capacity in human macrophage cell lines. The phenotype was rescued by wild-type SLC4A7, but not by SLC4A7 mutants, affecting transport capacity or cell surface localization. Loss of SLC4A7 resulted in increased cytoplasmic acidification during phagocytosis, suggesting that SLC4A7-mediated, bicarbonate-driven maintenance of cytoplasmic pH is necessary for phagosome acidification. Altogether, we identify SLC4A7 and bicarbonate-driven cytoplasmic pH homeostasis as an important element of phagocytosis and the associated microbicidal functions in macrophages.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.chom.2018.04.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6002608PMC
June 2018