Biology subjects

Engels, S.

Publications and source records attributed to Engels, S..

6 recordsLinked to original sources

bioRxiv2025

Proximity labeling reveals ZFP36L1 as a central hub for post-transcriptional regulation networks in T cells

Effective T cell responses against pathogens require a rapid yet tightly controlled remodeling of the proteome, and RNA binding proteins (RBPs) are key in this process. For instance, the RBP ZFP36L1 prevents excessive protein production and thereby limits immunopathology. ZFP36L1 is primarily known to mediate mRNA decay, but it can also regulate other processes. How its mode of action relates to its interaction partners is, however, not well-understood. Here, we mapped the ZFP36L1 interactome in primary human T cells. Using proximity labeling, we identified known and new interactors that regulate 3UTR-mediated RNA degradation, deadenylation, stress granule/p-body formation, as well as 5UTR-mediated translation repression and mRNA decapping. Snapshot analysis uncovered the ZFP36L1 interactome dynamics and RNA (in)dependency throughout T cell activation. Intriguingly, proximity labeling also uncovered regulators of ZFP36L1 protein expression: This included the helicase UPF1, which not only interacts with ZFP36L1 protein but also promotes its protein expression. Altogether, this comprehensive interactome map underlines the versatility of interactions with ZFP36L1 and their possible role in cellular function.

molecular biology↗

bioRxiv2024

Regulation of IFNgamma production by ZFP36L2 in T cells is context-dependent

CD8+ T cells kill target cells by releasing cytotoxic molecules and pro-inflammatory cytokines, such as TNF and IFN{gamma}. The magnitude and duration of cytokine production is defined by post-transcriptional regulation, and a critical regulator herein are RNA-binding proteins (RBPs). Although the functional importance of RBPs in regulating cytokine production is established, the kinetics and mode of action through which RBPs control cytokine production is not well understood. Previously, we showed that the RBP ZFP36L2 blocks translation of pre-formed cytokine encoding mRNA in quiescent memory T cells. Here, we uncover that ZFP36L2 regulates cytokine production in a context-dependent manner. T cell-specific deletion of ZFP36L2 (CD4-cre) had no effect on T cell development, or on cytokine production during early time points (2-6h) of T cell activation. In contrast, ZFP36L2 specifically dampened the production of IFN{gamma} during prolonged T cell activation (20-48h). ZFP36L2 deficiency also resulted in increased production of IFN{gamma} production in tumour-infiltrating T cells that are chronically exposed to antigen. Mechanistically, ZFP36L2 regulates IFN{gamma} production at late time points of activation by destabilizing Ifng mRNA in an AU-rich element-dependent manner. Together, our results reveal that ZFP36L2 employs different regulatory nodules in effector and memory T cells to regulate cytokine production.

immunology↗

bioRxiv2021

Effects of sub-lethal single, simultaneous, and sequential abiotic stresses on phenotypic traits of Arabidopsis thaliana

Plant responses to abiotic stresses are complex and dynamic, and involve changes in different traits, either as the direct consequence of the stress, or as an active acclimatory response. Abiotic stresses frequently occur simultaneously or in succession, rather than in isolation. Despite this, most studies have focused on a single stress and single or few plant traits. To address this gap, our study comprehensively and categorically quantified the individual and combined effects of three major abiotic stresses associated with climate change (flooding, progressive drought and high temperature) on 12 phenotypic traits related to morphology, development, growth and fitness, at different developmental stages in four Arabidopsis thaliana accessions. Combined sub-lethal stresses were applied either simultaneously (high temperature and drought) or sequentially (flooding followed by drought). In total, we analyzed the phenotypic responses of 1782 individuals across these stresses and different developmental stages. Overall, abiotic stresses and their combinations resulted in distinct patterns of effects across the traits analyzed, with both quantitative and qualitative differences across accessions. Stress combinations had additive effects on some traits, whereas clear positive and negative interactions were observed for other traits: 9 out of 12 traits for high temperature and drought, 6 out of 12 traits for post-submergence and drought showed significant interactions. In many cases where the stresses interacted, the strength of interactions varied across accessions. Hence, our results indicated a general pattern of response in most phenotypic traits to the different stresses and stress combinations, but it also indicated a natural genetic variation in the strength of these responses. Overall, our study provides a rich characterization of trait responses of Arabidopsis plants to sub-lethal abiotic stresses at the phenotypic level and can serve as starting point for further in-depth physiological research and plant modelling efforts.

plant biology↗

bioRxiv2021

Time-dependent regulation of cytokine production by RNA binding proteins defines T cell effector function

Potent T cell responses against infections and malignancies depend on the release of effector molecules, such as pro-inflammatory cytokines. Because effector molecules can be toxic, their production is tightly regulated through post-transcriptional events at 3 Untranslated Regions (3UTRs). RNA binding proteins (RBPs) were shown to be key regulators herein. With an RNA aptamer-based capture assay from human T cells, we identified >130 RBPs interacting with the IFNG, TNF and IL2 3UTRs in human T cells. T cell activation altered RBP-RNA interactions, revealing that RBP-target mRNA interactions rapidly respond to stimulation. Furthermore, we uncovered the intricate and time-dependent regulation of cytokine production by RBPs: whereas HuR supports early cytokine production, ZFP36L1, ATXN2L and ZC3HAV1 dampen and shorten the production duration, each at different time points. Strikingly, even though ZFP36L1 deletion did not phenotypically rescue T cell dysfunction in tumors, the increased production of cytokines and cytotoxic molecules resulted in superior anti-tumoral T cell responses in vivo. Our findings thus show that identifying RBP-RNA interactions reveals key modulators of T cell responses in health and disease.

immunology↗

bioRxiv2019

m6A methylation potentiates cytosolic dsDNA recognition in a sequence-specific manner

Nucleic acid sensing through pattern recognition receptors is critical for immune recognition of microbial infections. Microbial DNA is frequently methylated at the N6 position of adenines (m6A), a modification that is rare in mammalian host DNA. We show that m6A-methylation of 5-GATC-3 motifs augments the immunogenicity of double stranded (ds)DNA in macrophages and dendritic cells. Transfection with m6A-methylated DNA increased the expression of the activation markers CD69 and CD86, and of Ifn{beta}, iNos and Cxcl10 mRNA. Recognition of m6A DNA occurs independently of TLR and RIG-I signaling but requires STING, a key mediator of cytosolic DNA sensing. Intriguingly, the response to m6A DNA is sequence-specific. m6A is immunostimulatory in some motifs, but immunosuppressive in others, a feature that is conserved between mouse and human. In conclusion, epigenetic alterations of bacterial DNA are differentially perceived by innate cells, a feature that could potentially be used for the design of immune-modulating therapeutics.

immunology↗

bioRxiv2018

Circular RNA expression in human hematopoietic cells is widespread and cell-type specific

Hematopoietic stem cells differentiate into a broad range of specialized blood cells. This process is tightly regulated and depends on transcription factors, micro-RNAs, and long non-coding RNAs. Recently, also circular RNA (circRNA) were found to regulate cellular processes. Their expression pattern and their identity is however less well defined. Here, we provide the first comprehensive analysis of circRNA expression in human hematopoietic progenitors, and in differentiated lymphoid and myeloid cells. We here show that the expression of circRNA is cell-type specific, and increases upon maturation. circRNA splicing variants can also be cell-type specific. Furthermore, nucleated hematopoietic cells contain circRNA that have higher expression levels than the corresponding linear RNA. Enucleated blood cells, i.e. platelets and erythrocytes, were suggested to use RNA to maintain their function, respond to environmental factors or to transmit signals to other cells via microvesicles. Here we show that platelets and erythrocytes contain the highest number of circRNA of all hematopoietic cells, and that the type and numbers of circRNA changes during maturation. This cell-type specific expression pattern of circRNA in hematopoietic cells suggests a hithero unappreciated role in differentiation and cellular function.

immunology↗