Biology subjects

Engels, Z.

Publications and source records attributed to Engels, Z..

4 recordsLinked to original sources

bioRxiv2026

ZDHHC17–Mediated Palmitoylation of Hepatitis E Virus ORF3 Protein Regulates Vectorial Trafficking in Polarized Epithelial Cells

The hepatitis E virus (HEV) is a leading cause of acute hepatitis worldwide and is transmitted enterically along the gut-liver axis. Epithelial cell polarity in the gut and liver plays a critical role in HEV transmission. In intestinal epithelial cells, HEV enters through the apical membrane and is released basolaterally to access the bloodstream, whereas in hepatocytes, the virus enters basolaterally and is secreted apically into the bile duct. In this study, we sought to identify the viral and host determinants governing directional HEV secretion in both tissue types. Using polarized intestinal and hepatocyte models, we found that the small phosphoprotein ORF3, which is essential for progeny secretion, localizes predominantly to the apical membrane, in contrast to the ORF2 capsid protein. We further identified the palmitoyltransferase ZDHHC17 as a specific ORF3 interactor that mediates its apical localization and promotes HEV progeny release. Using automated cell segmentation and quantitative image analysis, we screened a panel of ORF3 mutants and found that positively charged residues within the N-terminus regulate membrane association. In addition, we identified a conserved PIFIQP motif that mediates the critical interaction with the ankyrin repeat domain (ARD) of ZDHHC17. Leveraging this interaction, we generated high-confidence structural models of ORF3 in complex with the ZDHHC17 ARD using AlphaFold. These models, further validated by molecular dynamics simulations, revealed additional ORF3 residues involved in the interaction. Collectively, our findings define key mechanisms underlying directional HEV release and provide broader insights into trafficking processes in polarized epithelial cells.

Cell Biology↗

bioRxiv2026

Herpes simplex virus infection promotes ALS pathology through ICP0-mediated PML body disruption

Transactive response DNA binding protein 43 kDa (TDP-43) pathology, is a central molecular hallmark of amyotrophic lateral sclerosis (ALS). However, the underlying triggers are incompletely understood. Here, we show that infection with herpes simplex virus (HSV) induces molecular hallmarks of ALS in various in vitro and in vivo models and is associated with an increased risk of ALS in human population data. German healthcare provider data (n = 238,440) and herpesvirus serology of an ALS patient and control cohort (n = 1,100) showed that HSV infection elevated the ALS risk by 210% and odds by [~]65%, respectively. On a molecular level, HSV infection promoted TDP-43 pathology in neuronal cell models, human iPSC-derived motoneurons and cerebral organoids, mice, and human tissue sections. This effect was triggered by HSV-1 or 2, but not by several other related herpesviruses. Mechanistically, the infected cell protein 0 (ICP0) of HSV-1/2 drives TDP-43 pathology by disturbance of promyelocytic leukemia nuclear bodies (PML-NBs), thereby abrogating TDP-43 SUMO2/3ylation. Taken together, we reveal a previously unrecognized association between HSV infection and ALS and clarify the underlying molecular mechanism that drives TDP-43 pathology. Our data may guide future studies into therapeutic and prophylactic interventions against ALS.

neuroscience↗

bioRxiv2025

Respiratory viruses activate autophagy via the IFN-STAT1/STAT5B-SOCS1 axis

Autophagy is an ancient catabolic process that has emerged as part of the innate immunity. Upon infection, autophagy is activated but key factors responsible remained unclear. Here, we show that interferon (IFN) released during viral infections subsequently activates autophagy via STAT1/5B-mediated upregulation of SOCS1. Our data shows that scavenging of IFNs diminishes autophagy induced by several respiratory viruses. All types of IFN (I, II and III) mediated robust autophagic flux activation in both cell lines and primary human lung fibroblasts in a JAK1-3 dependent manner. Depletion or pharmacological inhibition of individual STAT transcription factors demonstrated that both STAT1 and STAT5B are required for IFN-induced autophagy. Upon IFN stimulation STAT1 and STAT5B associate and translocate to the nucleus. Transcriptome analyses revealed that inhibition of STAT5 only reduces expression of a subset of IFN-stimulated genes, whereas most known anti-viral IFN-stimulated genes remain induced to high levels. Among the STAT5 dependent genes was Suppressor of Cytokine Signaling 1 (SOCS1). Overexpression of SOCS1 stimulated autophagy, whereas its depletion impaired IFN-induced autophagy. Successful viruses like measles virus (MeV) or respiratory syncytial viruses (RSV) evolved strategies to exploit autophagy to promote their own replication. Uncoupling IFN-mediated ISG defenses from autophagy induction using by STAT5 inhibition reduced virus-induced autophagy, and inhibited efficient replication of autophagy-dependent MeV and RSV. Taken together, our data show that IFN promotes autophagy via STAT1/STAT5B-SOCS1 in viral infections and reveal that targeting of this axis allows inhibition of autophagy-dependent viruses without compromising innate immune defenses. Author summaryAutophagy, like the Interferon (IFN) system, is considered part of the innate immune defenses that are activated upon viral infection. However, some viruses--like measles (MeV) and respiratory syncytial virus (RSV)--have learned to hijack this process to promote their replication. Our study shows that autophagy activation upon viral infections is promoted by the IFN system. Consequently, blocking IFNs reduced virus-induced autophagy. Mechanistic analyses demonstrated that various types of IFN induce expression of SOCS1, via the transcription factors STAT1 and STAT5B in cell lines and primary human lung cells. Pharmacological inhibition or depletion of STAT1, STAT5B or SOCS1 impaired IFN-induced autophagy. Importantly, disrupting STAT5 signaling does not impact IFN-mediated induction of the large majority of ISGs. Thus, selective disruption of IFN-induced autophagy by inhibiting STAT5 restricted replication of MeV and RSV. Our findings reveal an underappreciated mechanistic link between the IFN system and autophagy and suggest that targeting of the STAT5-SOCS1 axis may inhibit autophagy-dependent viruses without compromising IFN-mediated defenses.

microbiology↗

bioRxiv2023

A high-content RNA-based imaging assay reveals integrin beta 1 as a cofactor for cell entry of non-enveloped hepatitis E virus

Hepatitis E virus (HEV) is a major cause of acute hepatitis and mainly transmitted faecal-orally. HEV particles in faeces are non-enveloped, while those in the blood possess a cell-derived lipid envelope. Despite being a global health concern, there is limited understanding of the steps in the HEV life cycle, particularly cell entry. A previous study proposed integrin alpha 3 (ITGA3) as a potential host factor for nHEV entry, but the {beta}-integrin partner that co-mediates HEV entry has not been described. To address this knowledge gap and resolve the existing controversies surrounding HEV cell entry, we developed an RNA-FISH-based high-content imaging assay alllowing investigation of the entry pathways of both naked and enveloped HEV particles. Our observations indicate that naked HEV particles interact with the surface receptor integrin beta 1 (ITGB1), which likely facilitates their trafficking through the recycling endosome. In contrast, enveloped HEV particles do not interact with ITGB1 and instead use the classical endocytic pathway via the early endosome. Importantly, both forms of HEV require endosomal acidification and proteolytic cleavage by lysosomal cathepsins, which ultimately results in delivery of the HEV genome to the cytoplasm.

microbiology↗