Biology subjects

Daelemans, D.

Publications and source records attributed to Daelemans, D..

5 recordsLinked to original sources

bioRxiv2026

Unravelling resistance mechanisms of oncolytic viruses in glioblastoma

Glioblastoma (GBM) is an aggressive primary brain tumor with a major unmet medical need. Oncolytic viruses (OVs) show promise for GBM treatment, but complete remissions remain rare. The intratumoral heterogeneity of GBM drives therapeutic escape and emergence of OV-resistant subclones. Beyond the well-characterized interferon-mediated antiviral response, mechanisms driving OV resistance remain poorly understood. To identify new markers of tumor-intrinsic OV resistance in GBM, we exposed 14 GBM patient-derived cell lines (GBM-PDCLs) to 6 OVs and generated virus-resistant subpopulations from surviving cells. Focusing on Sindbis (SINV)- and H1-parvovirus (H1PV)-resistant cells, we showed that resistance is associated with impaired viral replication. Gene set enrichment analysis of transcriptomic profiles revealed that resistance to both SINV and H1PV correlated with downregulated glutamate receptor signaling. In contrast, collagen fibril organization was downregulated in SINV-resistant GBM PDCLs but upregulated in H1PV-resistant cells. Functional validation confirmed opposing effects of collagen degradation on SINV and H1PV oncolytic activity. One SINV-resistant GBM-PDCL showed cross-resistance to multiple OVs, which was associated with increased expression of antiviral immunity genes and increased dependence on type I interferon signaling for survival. Together, these findings reveal shared and virus-specific cellular processes driving OV resistance in GBM, providing a basis for strategies to overcome resistance.

cancer biology↗

bioRxiv2024

Allosteric degraders induce CRL5ASB8 mediated degradation of XPO1

SummaryThe nuclear export receptor exportin 1 (XPO1/CRM1) is often overexpressed in cancer cells, leading to the mislocalization of numerous cancer-related protein cargoes1,2. Selinexor, a covalent XPO1 inhibitor, and other Selective Inhibitor of Nuclear Export (SINEs) restore proper nuclear localization by blocking XPO1-cargo binding2-7. SINEs also induce XPO1 degradation via the Cullin-RING E3 ubiquitin ligase (CRL) substrate receptor ASB87. Here we elucidate the mechanism underlying the high-affinity engagement of CRL5ASB8 with SINE-conjugated XPO1. Cryogenic electron microscopy (cryoEM) structures reveal that ASB8 binds to a cryptic site on XPO1, which becomes accessible only upon SINE conjugation. While molecular glue degraders typically interact with both CRL and the substrate8-10, SINEs bind to XPO1 without requiring interaction with ASB8 for efficient XPO1 degradation. Instead, an allosteric mechanism facilitates high affinity XPO1-ASB8 interaction, leading to XPO1 ubiquitination and degradation. ASB8-mediated degradation is also observed upon treatment of the endogenous itaconate derivate 4-octyl itaconate, which suggests a native mechanism that is inadvertently exploited by synthesized XPO1 inhibitors. This allosteric XPO1 degradation mechanism of SINE compounds expands the known modes of targeted protein degradation beyond the well-characterized molecular glue degraders and proteolysis targeting chimeras of CRL4.

cancer biology↗

bioRxiv2023

Aberrant N-glycosylation in pathogenic variants of adenosine deaminase 2 underlying human ADA2 deficiency

Human deficiency of adenosine deaminase 2 (DADA2) is an autoinflammatory disease caused by pathogenic variants in ADA2 that lead to impaired deaminase activity. Recently, a lysosomal function of ADA2 has been proposed but an intracellular form of the protein has not yet been characterized. Here, we analyze protein expression of mutant ADA2 in human monocyte-derived macrophages from 10 DADA2 patients. We identify an intracellular low-molecular-weight (LMW) form of ADA2 that undergoes glycan trimming by -mannosidases and is absent in DADA2 macrophages. Subcellular fractionation and immunofluorescence microscopy demonstrate that LMW-ADA2 is localized in the lysosomes. By overexpression of 34 ADA2 variants in HEK293T and U-937 cells, we show that absence of LMW-ADA2 strongly correlates with reduced deaminase activity and predicts variant pathogenicity. In conclusion, we describe a previously unreported intracellular hypoglycosylated form of ADA2 and establish the absence of this LMW-ADA2 as a cellular characteristic of DADA2. Thereby, we introduce a protein correlate of the recently described lysosomal form of ADA2. SummaryEhlers et al. demonstrate that mutant ADA2 fails to undergo glycan processing beyond the ER leading to the absence of intracellular low-molecular-weight (LMW) ADA2 in DADA2 patients macrophages. LMW-ADA2 localizes to the lysosomes and can be generated from extracellular wild-type ADA2.

immunology↗

bioRxiv2021

A modular platform for engineering function ofnatural and synthetic biomolecular condensates

Phase separation is emerging as a universal principle for how cells use dynamic subcompartmentalization to organize biochemical reactions in time and space1,2. Yet, whether the emergent physical properties of these biomolecular condensates are important for their biological function remains unclear. The intrinsically disordered protein PopZ forms membraneless condensates at the poles of the bacterium Caulobacter crescentus and selectively sequesters kinase-signaling cascades to regulate asymmetric cell division3-5. By dissecting the molecular grammar underlying PopZ phase separation, we find that unlike many eukaryotic examples, where unstructured regions drive condensation6,7, a structured domain of PopZ drives condensation, while conserved repulsive features of the disordered region modulate material properties. By generating rationally designed PopZ mutants, we find that the exact material properties of PopZ condensates directly determine cellular fitness, providing direct evidence for the physiological importance of the emergent properties of biomolecular condensates. Our work codifies a clear set of design principles illuminating how sequence variation in a disordered domain alters the function of a widely conserved bacterial condensate. We used these insights to repurpose PopZ as a modular platform for generating synthetic condensates of tunable function in human cells.

cell biology↗

bioRxiv2020

Identification of TMEM106B as proviral host factor for SARS-CoV-2

The ongoing COVID-19 pandemic is responsible for worldwide economic damage and nearly one million deaths. Potent drugs for the treatment of severe SARS-CoV-2 infections are not yet available. To identify host factors that support coronavirus infection, we performed genome-wide functional genetic screens with SARS-CoV-2 and the common cold virus HCoV-229E in non-transgenic human cells. These screens identified PI3K type 3 as a potential drug target against multiple coronaviruses. We discovered that the lysosomal protein TMEM106B is an important host factor for SARS-CoV-2 infection. Furthermore, we show that TMEM106B is required for replication in multiple human cell lines derived from liver and lung and is expressed in relevant cell types in the human airways. Our results identify new coronavirus host factors that may potentially serve as drug targets against SARS-CoV-2 or to quickly combat future zoonotic coronavirus outbreaks.

microbiology↗