Biology subjects

Sauer, A.

Publications and source records attributed to Sauer, A..

4 recordsLinked to original sources

bioRxiv2026

Gene duplication and retrotransposition diversify the antiviral repertoire of macaque IFITM proteins

Interferon-induced transmembrane (IFITM) proteins are broad-spectrum antiviral restriction factors that inhibit viral entry of diverse enveloped viruses. Comparative genomic studies have revealed extensive lineage-specific diversification of IFITM genes, yet the functional consequences of this diversification remain poorly understood. We previously identified an expanded IFITM repertoire in macaques consisting of the canonical IFITM proteins, IFITM1 and IFITM3, a duplicated IFITM3 paralog (IFITM3A), and two retrotransposed IFITM3-derived genes (IFITM3-R1 and IFITM3-R2). Here, we thoroughly characterized the antiviral activities, intracellular localization, and mechanisms of regulation of canonical and non-canonical macaque IFITMs against vesicular stomatitis virus (VSV), influenza A virus (IAV), Sendai virus, and HIV-1. IFITM3A exhibited enhanced antiviral activity relative to IFITM3, particularly against VSV and HIV-1. Comparative mutational analyses identified amino acid substitutions in IFITM3 that contribute to the enhanced antiviral phenotype of IFITM3A. In contrast, the retrocopy IFITM3-R1 exhibited markedly reduced expression due to lysosome-dependent protein turnover mediated by a PPxY motif and a unique lysine residue (K51). Alteration of these determinants increased IFITM3-R1 expression and selectively enhanced restriction of VSV and IAV. Although several macaque IFITMs reduced HIV-1 infectivity when expressed in producer cells, none significantly inhibited HIV-1 infection in target cells. Furthermore, differential incorporation of IFITMs into HIV-1 virions did not consistently correlate with antiviral activity, indicating that virion incorporation alone is insufficient to explain HIV-1 restriction. Together, these findings demonstrate that gene duplication and retrotransposition have generated a functionally diverse IFITM repertoire in macaques and provide insight into how evolutionary diversification expands innate antiviral defenses in primates. ImportanceIFITM proteins are broad-spectrum antiviral restriction factors that inhibit infection of numerous enveloped viruses. Although IFITM genes have undergone extensive diversification during mammalian evolution, the functional consequences of this diversification remain poorly understood. Here, we show that expansion of the macaque IFITM locus through gene duplication and retrotransposition generated proteins with distinct antiviral activities, intracellular localization patterns, and regulatory mechanisms. We identify amino acid determinants that contribute to the enhanced antiviral activity of the duplicated paralog IFITM3A and demonstrate that lysosome-dependent turnover mediated by a PPxY motif and a unique lysine residue limits expression and antiviral activity of the retrocopy IFITM3-R1. We further show that macaque IFITMs inhibit HIV-1 predominantly through producer-cell-dependent mechanisms and reveal that IFITM virion incorporation alone does not predict antiviral potency. These findings provide mechanistic insight into how restriction factor diversification expands innate antiviral defenses and shapes host-virus interactions in primates.

microbiology↗

bioRxiv2025

Scalable automated segmentation quantifies mitochondrial proteins and morphology at the nanoscale

Ultrastructural changes of mitochondria are closely associated with metabolic dysfunction, leading to a variety of human disorders. These changes can be visualized by pan-Expansion Microscopy (pan-ExM), a 3D microscopy technique requiring only standard fluorescence microscopes, at a throughput exceeding that of the current gold standard, 3D electron microscopy, by orders of magnitude. However, a lack of tools that enable the characterization and quantification of the observed ultrastructural features in the acquired 3D datasets at a comparable throughput has hindered the widespread adoption of pan-ExM for quantitative imaging. Here, we present an automated deep-learning based segmentation approach that utilizes pan-ExMs power to acquire multi-channel images and uses specific labeling as the annotation for the training of the segmentation network. This molecular annotation reduces the required manual annotation effort for mitochondria substructures to just a few hours when setting up the experiment and thereby provides access to 3D suborganellar morphology of mitochondria at an unprecedented throughput. Our approach, which we term MAPS (Mitochondrial Automated Pan-ExM Segmentation), enables for the first time to quantify mitochondrial ultrastructural morphology at scale. We demonstrate this power by characterizing the 3D mitochondrial morphology at the organelle and sub-organelle level in tens of HeLa cells under different treatments and localizing mitochondrial proteins in the sub-organellar context. To demonstrate our technology in tissue, we compare the ultrastructural morphology of mitochondria in proximal tubules of kidneys of mice exhibiting acute kidney injury (AKI) with those of untreated mice, revealing striking differences in their cristae structure. MAPS can easily be adapted to different cell and tissue types, allowing the analysis of tens of samples per day, and therefore provides a versatile tool for a comprehensive understanding of mitochondrial ultrastructural changes in many disease contexts. Requiring only standard fluorescence microscopes and computer infrastructure, MAPS is readily adoptable by any lab. HighlightsO_LIMAPS utilizes specific labeling to train a segmentation model for 3D super-resolution pan-ExM images C_LIO_LISuborganellar mitochondrial features and their changes in disease models are quantified at high throughput C_LIO_LI3D protein distributions are correlated to ultrastructural features in mitochondria C_LIO_LIRequiring only standard lab infrastructure, MAPS is readily adoptable C_LI

cell biology↗

bioRxiv2023

Extending ligand efficacy indices with compound pharmacokinetic characteristics towards holistic Compound Quality Scores

The suitability of a small molecule to become an oral drug is often assessed by simple physicochemical rules, the application of ligand efficacy scores (combining physicochemical properties with potency) or by multi-parameter composite scores based on physicochemical compound properties. These rules and scores are empirical and typically lack mechanistic background, such as information on pharmacokinetics (PK). We introduce a new type of Compound Quality Scores (specifically called dose-scores and cmax-scores), which explicitly include predicted or when available experimentally determined PK parameters, such as volume of distribution, clearance and plasma protein binding. Combined with on-target potency, these scores are surrogates for an estimated dose or the corresponding cmax. These Compound Quality Scores allow for prioritization of compounds in test cascades, and by integrating machine learning based potency and PK predictions, these scores allow prioritization for synthesis. We demonstrate the complementary and in most cases the superiority to existing efficiency metrics (such as ligand efficiency scores) by project examples.

pharmacology and toxicology↗

bioRxiv2018

Perceptual phenotypes: Perceptual gains and losses in synesthesia and schizophrenia

Individual differences in perception are widespread. Considering inter-individual variability, synesthetes experience stable additional sensations; schizophrenia patients suffer perceptual deficits in e.g. perceptual organization (alongside hallucinations and delusions). Is there a unifying principle explaining inter-individual variability in perception? There is good reason to believe perceptual experience results from inferential processes whereby sensory evidence is weighted by prior knowledge about the world. Different perceptual phenotypes may result from different precision weighting of sensory evidence and prior knowledge. We tested this hypothesis by comparing visibility thresholds in a perceptual hysteresis task across medicated schizophrenia patients, synesthetes, and controls. Participants rated the subjective visibility of stimuli embedded in noise while we parametrically manipulated the availability of sensory evidence. Additionally, precise long-term priors in synesthetes were leveraged by presenting either synesthesia-inducing or neutral stimuli. Schizophrenia patients showed increased visibility thresholds, consistent with overreliance on sensory evidence. In contrast, synesthetes exhibited lowered thresholds exclusively for synesthesia-inducing stimuli suggesting high-precision long-term priors. Additionally, in both synesthetes and schizophrenia patients explicit, short-term priors - introduced during the hysteresis experiment - lowered thresholds but did not normalize perception. Our results imply that distinct perceptual phenotypes might result from differences in the precision afforded to prior beliefs and sensory evidence, respectively.

neuroscience↗