Biology subjects

Grauvogel, L.

Publications and source records attributed to Grauvogel, L..

6 recordsLinked to original sources

bioRxiv2026

A genome-scale ORF screen for resilience factors that protect the RPE and restore vision in aged mice

Aging is a complex phenomenon, yet therapeutic discovery has largely relied on testing individual hypothesis-driven targets. Here, we performed a genome-scale open reading frame (ORF) screen for oxidative-stress resistance in retinal pigment epithelium (RPE) cells, which are vulnerable to oxidative damage during aging. The screen identified nine protective ORFs including antioxidant factors and an epithelial-to-mesenchymal transition regulator. Notably, we also identified three factors that reduce transcriptomic age including the cardiac transcription factor NKX2-5. NKX2-5 conferred robust oxidative resilience in vitro and in vivo. Domain dissection revealed that its homeodomain is dispensable for resilience, enabling development of NKX2-5{Delta}HD, which retained protective activity without detectable toxicity over 14 months. In middle-aged mice, subretinal NKX2-5{Delta}HD restored visual and electrophysiological function, and its systemic delivery improved grip strength and reduced frailty in late-aged mice. These findings highlight the value of unbiased, genome-scale gain-of-function screening, as resilience factors normally expressed in other contexts can be reengineered as potential therapeutics for age-related decline in other tissues.

genetics↗

bioRxiv2026

Combination of enhanced gene activation and cell death causes lethal inflammatory pulmonary fibrosis

The current paradigm of inflammatory disease etiology is that it is caused by an aberrant increase in either gene activation or cell death. Studying the linear ubiquitin (linUb) chain assembly complex (LUBAC) was instrumental in proving that immune-receptor-dependent cell death can cause inflammatory disease. As LUBAC regulates both, gene activation and cell death, it can, however, also serve to evaluate the inflammatory-disease-initiating role of gene activation. Investigating mice with two different gene-activation-enhancing point mutations in LUBAC components showed that aberrantly increased gene activation in Hoil 1C458A/C458A mice did not cause pathology. In contrast, in HoipN101A/N101A mice it led to untoward cell death which, unexpectedly, was required for pathological inflammation, culminating in lethal lung fibrosis resembling human idiopathic pulmonary fibrosis (IPF). Hence, we here uncover a new etiology of inflammation, whereby aberrantly enhanced gene activation can be root cause of pathological, fibrogenic inflammation, yet intriguingly via inducing untoward cell death.

cell biology↗

bioRxiv2026

The diverse functions of viral microproteins

A large fraction of the uncharacterized proteome consists of microproteins. Viruses, rich in microproteins with potent activities, provide a unique system for exploring their functions and evolution. Here, we systematically annotate viral microproteins through a phenotype-first approach: construction of a >50,000-element small ORF library spanning the microprotein-coding potential of human-infecting viruses, followed by broad screens that enrich candidates for high-resolution profiling by Perturb-seq, mass spectrometry, AI-guided structure prediction, and mechanistic studies. This atlas identified >2,000 active microproteins that modulate host pathways through diverse mechanisms, including molecular mimicry, hijacking of key regulators, and altering subcellular localization. We further show the oncogenic potential of BNLF2b, an uncharacterized Epstein-Barr virus microprotein linked to nasopharyngeal carcinoma. Three principles emerge: viral microproteins are diverse and often multifunctional, show widespread convergence toward shared functions, and serve as reservoirs of evolutionary innovation. These findings elucidate how viral microproteins occupy a large functional landscape, establish them as versatile tools for host manipulation, and provide a framework for functional annotation of uncharacterized proteins, contributing toward predictive systems virology.

systems biology↗

bioRxiv2026

HIP-MS: An ultra-high-throughput, sensitive, and versatile affinity enrichment platform for static and dynamic interactome profiling

Although protein-protein interactions govern virtually all cellular processes, systematic interactome mapping by affinity enrichment mass spectrometry (AE-MS) is constrained by manual sample preparation and lengthy liquid chromatography (LC)-MS/MS acquisition. Here we present High-throughput Interactome Profiling by MS (HIP-MS), an automated, end-to-end pipeline that overcomes these limitations. It leverages the compact, high-affinity ALFA tag for on-plate nanobody capture in 384-well format, combined with on-plate tryptic digestion. It can process almost 10,000 samples per week from protein expression up to MS measurement and can be combined with ultra-fast gradient LC-MS acquisition of 500 samples per day. HIP-MS remains sensitive down to low-microgram lysate inputs, a 4,000-fold reduction compared to recent large-scale screens. Our pipeline recovers complexes from diverse cellular compartments and resolves endogenous membrane receptor signaling. HIP-MS establishes a scalable foundation for systematic interrogation of protein interactions across conditions, perturbations, and time, and for the generation of large-scale datasets for computational modeling.

systems biology↗

bioRxiv2026

Scanning DIA on the ZenoTOF 8600 system enables ultra-sensitive and quantitative proteomics from single cells to post-translational modifications in a compact platform

Mass spectrometry-based proteomics increasingly demands platforms that combine quantitative rigor with the discovery capabilities of accurate mass systems. Here we present the ZenoTOF 8600 system, a compact mass spectrometry system that integrates enhanced ion capture and transmission optics with an optical detection system, Zeno trap-enhanced MS/MS, electron-activated dissociation, and scanning quadrupole data-independent acquisition (ZT Scan DIA). We show that ZT Scan DIA outperforms conventional variable-window DIA (Zeno SWATH DIA) in both identifications and quantitative reproducibility, and demonstrate the platforms versatility across proteomics applications: thousands of protein groups from bulk samples at up to 500 samples per day, single-cell proteomics yielding up to 4,700 proteins, accurate ratio recovery in mixed-species quantitative benchmarks, low-attomole targeted quantitation, and detection of disease-relevant phosphorylation in a Parkinsons disease cellular model using complementary CID and EAD fragmentation. The instruments compact footprint makes it attractive for settings where both analytical breadth and operational robustness are required.

biophysics↗

bioRxiv2024

Cardiomyocyte PGC-1α enables physiological adaptations to endurance exercise through suppression of GDF15 and cardiac atrophy

Exercise training induces physiological cardiac hypertrophy, enhanced mitochondrial biogenesis and myocardial contractility. In skeletal muscle, the transcriptional coactivator PGC-1 is a key orchestrator of these responses. The heart expresses abundant and exercise-responsive PGC-1, but it is unclear whether cardiomyocyte PGC-1 is necessary for cardiac adaptation to endurance training. Here we demonstrate that cardiomyocyte PGC-1 is required for physiological cardiac hypertrophy during exercise training in mice. In the absence of cardiomyocyte PGC-1, voluntary wheel running does not improve exercise capacity and instead confers immune-fibrotic-atrophic heart failure after just 6 weeks of training. We identify cardiomyocyte PGC-1 as a negative regulator of stress-responsive senescence gene expression. The most enriched of these is the myomitokine GDF15. GDF15 is secreted locally but not systemically in PGC-1-deficient mouse hearts and reduces cardiomyocyte size. Cardiomyocyte-specific reduction of GDF15 expression preserves exercise tolerance and cardiac contractility in PGC-1-deficient mice during endurance training. Finally, we show that cardiomyocyte PPARGC1A expression correlates with cardiomyocyte number and negatively with GDF15 expression in human cardiomyopathies through single nucleus RNA sequencing. Our data implicate cardiomyocyte PGC-1 as a vital safeguard against stress-induced atrophy and local GDF15-induced dysfunction during exercise.

physiology↗