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Published year: 20215
Natural isotope correction improves analysis of protein modification dynamics

Abstract (Expand)

Abstract Stable isotope labelling in combination with high-resolution mass spectrometry approaches are increasingly used to analyze both metabolite and protein modification dynamics. To enable correct …ynamics. To enable correct estimation of the resulting dynamics, it is critical to correct the measured values for naturally occurring stable isotopes, a process commonly called isotopologue correction or deconvolution. While the importance of isotopologue correction is well recognized in metabolomics, it has received far less attention in proteomics approaches. Although several tools exist that enable isotopologue correction of mass spectrometry data, the majority is tailored for the analysis of low molecular weight metabolites. We here present PICor which has been developed for isotopologue correction of complex isotope labelling experiments in proteomics or metabolomics and demonstrate the importance of appropriate correction for accurate determination of protein modifications dynamics, using histone acetylation as an example.

Authors: Jörn Dietze, Alienke van Pijkeren, Anna-Sophia Egger, Mathias Ziegler, Marcel Kwiatkowski, Ines Heiland

Date Published: 1st Dec 2021

Publication Type: Journal

Combining dictionary- and rule-based approximate entity linking with tuned BioBERT

Abstract (Expand)

Chemical named entity recognition (NER) is a significant step for many downstream applications like entity linking for the chemical text-mining pipeline. However, the identification of chemical entities … in a biomedical text is a challenging task due to the diverse morphology of chemical entities and the different types of chemical nomenclature. In this work, we describe our approach that was submitted for BioCreative version 7 challenge Track 2, focusing on the ‘Chemical Identification’ task for identifying chemical entities and entity linking, using MeSH. For this purpose, we have applied a two-stage approach as follows (a) usage of fine-tuned BioBERT for identification of chemical entities (b) semantic approximate search in MeSH and PubChem databases for entity linking. There was some friction between the two approaches, as our rule-based approach did not harmonise optimally with partially recognized words forwarded by the BERT component. For our future work, we aim to resolve the issue of the artefacts arising from BERT tokenizers and develop joint learning of chemical named entity recognition and entity linking using pre-trained transformer-based models and compare their performance with our preliminary approach. Next, we will improve the efficiency of our approximate search in reference databases during entity linking. This task is non-trivial as it entails determining similarity scores of large sets of trees with respect to a query tree. Ideally, this will enable flexible parametrization and rule selection for the entity linking search.

Authors: Ghadeer Mobasher, Lukrécia Mertová, Sucheta Ghosh, Olga Krebs, Bettina Heinlein, Wolfgang Müller

Date Published: 11th Nov 2021

Publication Type: Proceedings

The SZT2 Interactome Unravels New Functions of the KICSTOR Complex

Abstract (Expand)

Seizure threshold 2 (SZT2) is a component of the KICSTOR complex which, under catabolic conditions, functions as a negative regulator in the amino acid-sensing branch of mTORC1. Mutations in this gene …e cause a severe neurodevelopmental and epileptic encephalopathy whose main symptoms include epilepsy, intellectual disability, and macrocephaly. As SZT2 remains one of the least characterized regulators of mTORC1, in this work we performed a systematic interactome analysis under catabolic and anabolic conditions. Besides numerous mTORC1 and AMPK signaling components, we identified clusters of proteins related to autophagy, ciliogenesis regulation, neurogenesis, and neurodegenerative processes. Moreover, analysis of SZT2 ablated cells revealed increased mTORC1 signaling activation that could be reversed by Rapamycin or Torin treatments. Strikingly, SZT2 KO cells also exhibited higher levels of autophagic components, independent of the physiological conditions tested. These results are consistent with our interactome data, in which we detected an enriched pool of selective autophagy receptors/regulators. Moreover, preliminary analyses indicated that SZT2 alters ciliogenesis. Overall, the data presented form the basis to comprehensively investigate the physiological functions of SZT2 that could explain major molecular events in the pathophysiology of developmental and epileptic encephalopathy in patients with SZT2 mutations.

Authors: Cecilia Cattelani, Dominik Lesiak, Gudrun Liebscher, Isabel I. Singer, Taras Stasyk, Moritz H. Wallnöfer, Alexander M. Heberle, Corrado Corti, Michael W. Hess, Kristian Pfaller, Marcel Kwiatkowski, Peter P. Pramstaller, Andrew A. Hicks, Kathrin Thedieck, Thomas Müller, Lukas A. Huber, Mariana Eca Guimaraes de Araujo

Date Published: 1st Oct 2021

Publication Type: Journal

Hypoxia Routes Tryptophan Homeostasis Towards Increased Tryptamine Production.

Abstract (Expand)

The liver is the central hub for processing and maintaining homeostatic levels of dietary nutrients especially essential amino acids such as tryptophan (Trp). Trp is required not only to sustain protein … synthesis but also as a precursor for the production of NAD, neurotransmitters and immunosuppressive metabolites. In light of these roles of Trp and its metabolic products, maintaining homeostatic levels of Trp is essential for health and well-being. The liver regulates global Trp supply by the immunosuppressive enzyme tryptophan-2,3-dioxygenase (TDO2), which degrades Trp down the kynurenine pathway (KP). In the current study, we show that isolated primary hepatocytes when exposed to hypoxic environments, extensively rewire their Trp metabolism by reducing constitutive Tdo2 expression and differentially regulating other Trp pathway enzymes and transporters. Mathematical modelling of Trp metabolism in liver cells under hypoxia predicted decreased flux through the KP while metabolic flux through the tryptamine branch significantly increased. In line, the model also revealed an increased accumulation of tryptamines under hypoxia, at the expense of kynurenines. Metabolic measurements in hypoxic hepatocytes confirmed the predicted reduction in KP metabolites as well as accumulation of tryptamine. Tdo2 expression in cultured primary hepatocytes was reduced upon hypoxia inducible factor (HIF) stabilisation by dimethyloxalylglycine (DMOG), demonstrating that HIFs are involved in the hypoxic downregulation of hepatic Tdo2. DMOG abrogated hepatic luciferase signals in Tdo2 reporter mice, indicating that HIF stability also recapitulates hypoxic rewiring of Trp metabolism in vivo. Also in WT mice HIF stabilization drove homeostatic Trp metabolism away from the KP towards enhanced tryptamine production, leading to enhanced levels of tryptamine in liver, serum and brain. As tryptamines are the most potent hallucinogens known, the observed upregulation of tryptamine in response to hypoxic exposure of hepatocytes may be involved in the generation of hallucinations occurring at high altitude. KP metabolites are known to activate the aryl hydrocarbon receptor (AHR). The AHR-activating properties of tryptamines may explain why immunosuppressive AHR activity is maintained under hypoxia despite downregulation of the KP. In summary our results identify hypoxia as an important factor controlling Trp metabolism in the liver with possible implications for immunosuppressive AHR activation and mental disturbances.

Authors: S. R. Mohapatra, A. Sadik, S. Sharma, G. Poschet, H. M. Gegner, T. V. Lanz, P. Lucarelli, U. Klingmuller, M. Platten, I. Heiland, C. A. Opitz

Date Published: 8th Mar 2021

Publication Type: Journal

Finding new edges: systems approaches to MTOR signaling.

Abstract (Expand)

Cells have evolved highly intertwined kinase networks to finely tune cellular homeostasis to the environment. The network converging on the mechanistic target of rapamycin (MTOR) kinase constitutes a … central hub that integrates metabolic signals and adapts cellular metabolism and functions to nutritional changes and stress. Feedforward and feedback loops, crosstalks and a plethora of modulators finely balance MTOR-driven anabolic and catabolic processes. This complexity renders it difficult - if not impossible - to intuitively decipher signaling dynamics and network topology. Over the last two decades, systems approaches have emerged as powerful tools to simulate signaling network dynamics and responses. In this review, we discuss the contribution of systems studies to the discovery of novel edges and modulators in the MTOR network in healthy cells and in disease.

Authors: A. M. Heberle, U. Rehbein, M. Rodriguez Peiris, K. Thedieck

Date Published: 26th Feb 2021

Publication Type: Journal

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