Biology subjects

Schmidt, I.

Publications and source records attributed to Schmidt, I..

5 recordsLinked to original sources

bioRxiv2026

Staphylococcus aureus enhances influenza A virus replication through modulation of host cell vesicular transport

Influenza A virus (IAV) is a major respiratory pathogen that causes substantial morbidity and mortality worldwide. A significant complication of primary IAV infection is secondary bacterial co-infection. Here, we report that Staphylococcus aureus enhances IAV replication through the activity of the surface protein fibronectin-binding protein A (FnbA). The pro-viral activity of FnbA is conserved across multiple IAV strains and is associated with reduced abundance of the host vesicular trafficking proteins VPS26A and VTA1. FnbA does not substantially increase viral protein abundance or alter intracellular distribution. Instead, pro-viral activity is associated with a greater proportion of infectious progeny particles and increased release of infectious virions from infected cells. Thus, we identify FnbA as a bacterial factor that enhances IAV replication and demonstrate that S. aureus can manipulate host cell processes to promote the production and release of infectious virus.

microbiology↗

bioRxiv2024

Demographic responses to climatic changes during the Final Palaeolithic in Europe

The European Final Palaeolithic witnessed marked changes in almost all societal domains. Despite a rich body of evidence, our knowledge of palaeodemographic processes and regional population dynamics still needs to be improved. In this study, we present regionally differentiated estimates of absolute numbers and population densities for the Greenland Interstadial 1d-a (GI-1d-a; 14-12.7 ka BP) and the Greenland Stadial 1 (GS-1; 12.7-11.6 ka BP) for Southern, Western, Northern and Central Europe. The data were obtained by applying the Cologne Protocol, a geostatistical approach for estimating prehistoric population size and density, to a newly compiled dataset of Final Palaeolithic sites. On a large spatio-temporal scale, we observe a shift of the main areas of human occupation from the Franco-Cantabrian region, which was intensely occupied during most phases of the preceding Upper Palaeolithic, to regions north of the Alps. At smaller scales, we observe divergent regional trends in the Final Palaeolithic meta-population: during GI 1d-a, a decreasing population in southwestern Europe and an increasing population in north-eastern Central Europe. For the first time since the dispersal of anatomically modern humans into Europe, we see that Central Europe becomes the dominant demographic growth area. Subsequently, the climatic cooling of GS-1 coincides with a pronounced population decline in most parts of the study area. An apparent increase in population density occurs only in north-eastern Central Europe and north-eastern Italy. Our estimates suggest that the total population was reduced by half. Similar results, with a relationship between decreasing temperatures and decreasing populations, have already been observed for the late phase of the Gravettian, when populations were reduced to only one third of those estimated for the early phase. Yet, in contrast to the collapse of local populations during the late Gravettian, the increase in population densities in Central Europe during GS-1 indicates population movements eastwards, possibly in response to deteriorating climatic conditions, particularly in western regions during the Younger Dryas.

ecology↗

bioRxiv2023

Convergence of multiple RNA-silencing pathways on GW182/TNRC6

The RNA-binding protein TRIM71/LIN-41 is a phylogenetically conserved developmental regulator that functions in mammalian stem cell reprogramming, brain development and cancer. TRIM71 recognizes target mRNAs through hairpin motifs and silences them through molecular mechanisms that await identification. Here, we uncover that TRIM71 silences its targets by recruiting TNRC6/GW182, a core component of the miRNA-induced silencing complex (miRISC). Co-immunoprecipitation reveals interaction of TNRC6A with additional RNA-binding proteins and we demonstrate that AGO2, TRIM71, and UPF1 each recruit TNRC6 to specific, largely distinct sets of transcripts to silence them. As cellular TNRC6 levels are limiting, competition occurs among the silencing pathways, such that loss of AGO2 protein, or of AGO2 binding to TNRC6, enhances the activities of the other pathways. We conclude that a miRNA-like silencing activity is shared among different mRNA silencing pathways and that use of TNRC6 as a central hub provides a means to integrate their activities.

molecular biology↗

bioRxiv2023

A novel HERC4-dependent glue degrader targeting STING

Stimulator of interferon genes (STING) is a central component of the pathway sensing the presence of cytosolic nucleic acids, having a key role in type I interferon innate immune response. Localized at the endoplasmic reticulum (ER), STING becomes activated by cGAMP, which is generated by the intracellular DNA sensor cyclic GMP-AMP synthase (cGAS). Due to its critical role in physiological function and its involvement in a variety of diseases, STING has been a notable focus for drug discovery. Recent advances in drug discovery allow the targeting of proteins previously considered "un-druggable" by novel mechanism of actions. Molecular glue degraders are defined as the compounds leading targeted protein degradation (TPD) by creating novel ligase-substrate interactions. Here, we identified AK59 as a novel molecular glue degrader for STING. A genome-wide, CRISPR/Cas9 knockout screen showed that the compound-mediated degradation of STING by AK59 is compromised by the loss of HECT and RLD domain containing E3 ubiquitin protein ligase 4 (HERC4), ubiquitin-like modifier activating enzyme 5 (UBA5) and ubiquitin like modifier activating enzyme 6 (UBA6). While UBA5 and UBA6 could be the auxiliary factors for AK59 activity, our results indicate that HERC4 is the main E3 ligase for the observed degradation mechanism. Validation by individual CRISPR knockouts, co-immunoprecipitations, as well as proximity mediated reporter assays suggested that AK59 functions as a glue degrader by forming a novel interaction between STING and HERC4. Furthermore, our data reveals that AK59 was effective on the most common pathological STING mutations that cause STING-associated vasculopathy with onset in infancy (SAVI), suggesting a potential clinical application of this mechanism. Thus, these findings not only reveal a novel mechanism for compound-induced degradation of STING but also utilize HERC4 as potential E3 ligase that for TPD, enabling novel therapeutic applications.

molecular biology↗

bioRxiv2023

Drug-induced eRF1 degradation promotes readthrough and reveals a new branch of ribosome quality control

Suppression of premature termination codons (PTC) by translational readthrough is a promising strategy to treat a wide variety of severe genetic diseases caused by nonsense mutations. Here, we present two novel and potent readthrough promoters - NVS1.1 and NVS2.1 - that restore substantial levels of functional full-length CFTR and IDUA proteins in disease models for cystic fibrosis and Hurler syndrome, respectively. In contrast to other readthrough promoters that affect stop codon decoding, the NVS compounds stimulate PTC suppression by triggering rapid proteasomal degradation of the translation termination factor eRF1. Our results show that this occurs by trapping eRF1 in the terminating ribosome, causing ribosome stalls and subsequent ribosome collisions, activating a novel branch of the ribosome-associated quality control (RQC) network that involves the translational stress sensor GCN1 and the catalytic activity of the E3 ubiquitin ligases RNF14 and RNF25.

molecular biology↗