Tzouros, M. | bioRxiv Science

bioRxiv2023

Kinex infers causal kinases from phosphoproteomics data

MotivationPhosphoproteomics data are essential for characterising signalling pathways, identifying drug targets, and evaluating efficacy and safety profiles of drug candidates. Emerging resources, including a substrate-specificity atlas and drug-induced phosphoproteomics profiles, may transform the inference of causal kinases. However, there is currently no open-source software that leverages insights derived from these resources. ResultsWe introduce Kinex, a workflow implemented in the same-name Python package, which infers causal serine/threonine kinases from phosphoproteomics data. Kinex allows users to score kinase-substrate interactions, perform enrichment analysis, visualise candidates of causal regulators, and query similar profiles in a database of drug-induced kinase activities. Analysing seven published studies and one newly generated dataset, we demonstrate that analysis with Kinex recovers causal effects of perturbations and reveals novel biological insights. We foresee that Kinex will become an indispensable tool for basic and translational research including drug discovery. AvailabilityKinex is released with the GNU General Public License and available at https://github.com/bedapub/kinex.

bioinformatics↗

bioRxiv2020

Alternative splicing liberates a cryptic cytoplasmic isoform of mitochondrial MECR that antagonizes influenza virus

Viruses must balance their reliance on host cell machinery for replication while avoiding host defense. Influenza A viruses are zoonotic agents that frequently switch hosts, causing localized outbreaks with the potential for larger pandemics. The host range of influenza virus is limited by the need for successful interactions between the virus and cellular partners. Here we used immuno-competitive capture-mass spectrometry to identify cellular proteins that interact with human- and avian-style viral polymerases. We focused on the pro-viral activity of heterogenous nuclear ribonuclear protein U-like 1 (hnRNP UL1) and the anti-viral activity of mitochondrial enoyl CoA-reductase (MECR). MECR is localized to mitochondria where it functions in mitochondrial fatty acid synthesis (mtFAS). While a small fraction of the polymerase subunit PB2 localizes to the mitochondria, PB2 did not interact with full-length MECR. By contrast, a minor splice variant produces cytoplasmic MECR (cMECR) that interacts with PB2. cMECR binds the viral polymerase and suppresses viral replication by blocking assembly of viral ribonucleoprotein complexes (RNPs). MECR ablation through genome editing or drug treatment is detrimental for cell health, creating a generic block to virus replication. Using the yeast homolog Etr1 to supply the metabolic functions of MECR in MECR-null cells, we showed that specific antiviral activity is independent of mtFAS and lies solely within cMECR. Thus, alternative splicing produces a cryptic antiviral protein that is embedded within a key metabolic enzyme.

microbiology↗