Biology subjects

Schoenherr, C.

Publications and source records attributed to Schoenherr, C..

5 recordsLinked to original sources

bioRxiv2023

TGM6, a helminth secretory product, mimics TGF-β binding to TβRII to antagonize TGF-β signaling in fibroblasts

The murine helminth parasite Heligmosomoides polygyrus expresses a family of proteins structurally related to TGF-{beta} Mimic 1 (TGM1), a secreted five domain protein that activates the TGF-{beta} pathway and converts naive T lymphocytes to immunosuppressive Tregs. TGM1 signals through the TGF-{beta} type I and type II receptors, T{beta}RI and T{beta}RII, with domains 1-2 and 3 binding T{beta}RI and T{beta}RII, respectively, and domains 4-5 binding CD44, a co-receptor abundant on T cells. TGM6 is a homologue of TGM1 that is co-expressed with TGM1, but lacks domains 1 and 2. Herein, we show that TGM6 binds T{beta}RII through domain 3, but does not bind T{beta}RI, or other type I or type II receptors of the TGF-{beta} family. In TGF-{beta} reporter assays in fibroblasts, TGM6, but not truncated TGM6 lacking domains 4 and 5, potently inhibits TGF-{beta}- and TGM1-induced signaling, consistent with its ability to bind T{beta}RII but not T{beta}RI or other receptors of the TGF-{beta} family. However, TGM6 does not bind CD44 and is unable to inhibit TGF-{beta} and TGM1 signaling in T cells. To understand how TGM6 binds T{beta}RII, the X-ray crystal structure of the TGM6 domain 3 bound to T{beta}RII was determined at 1.4 [A]. This showed that TGM6 domain 3 binds T{beta}RII through an interface remarkably similar to the TGF-{beta}:T{beta}RII interface. These results suggest that TGM6 has adapted its domain structure and sequence to mimic TGF-{beta} binding to T{beta}RII and function as a potent TGF-{beta} and TGM1 antagonist in fibroblasts. The coexpression of TGM6, along with the immunosuppressive TGMs that activate the TGF-{beta} pathway, may prevent tissue damage caused by the parasite as it progresses through its life cycle from the intestinal lumen to submucosal tissues and back again.

biochemistry↗

bioRxiv2023

The helminth TGF-beta mimic TGM4 is a modular ligand that binds CD44, CD49d and TGF-beta receptors to preferentially target myeloid cells

The murine helminth parasite Heligmosomoides polygyrus expresses a family of modular proteins which, replicating the functional activity of the immunomodulatory cytokine TGF-{beta}, have been named TGM (TGF-{beta} Mimic). Multiple domains bind to different receptors, including TGF-{beta} receptors T{beta}RI (ALK5) and T{beta}RII through domains 1-3, and prototypic family member TGM1 binds the cell surface co-receptor CD44 through domains 4-5. This allows TGM1 to induce T lymphocyte Foxp3 expression, characteristic of regulatory (Treg) cells, and to activate a range of TGF-{beta}-responsive cell types. In contrast, a related protein, TGM4, targets a much more restricted cell repertoire, primarily acting on myeloid cells, with less potent effects on T cells and lacking activity on other TGF-{beta}-responsive cell types. TGM4 binds avidly to myeloid cells by flow cytometry, and can outcompete TGM1 for cell binding. Analysis of receptor binding in comparison to TGM1 reveals a 10-fold higher affinity than TGM1 for TGF{beta}R-I (T{beta}RI), but a 100-fold lower affinity for T{beta}RII through Domain 3. Consequently, TGM4 is more dependent on co-receptor binding; in addition to CD44, TGM4 also engages CD49d (Itga4) through Domains 1-3, as well as CD206 and Neuropilin-1 through Domains 4 and 5. TGM4 was found to effectively modulate macrophage populations, inhibiting lipopolysaccharide-driven inflammatory cytokine production and boosting interleukin (IL)-4-stimulated responses such as Arginase-1 in vitro and in vivo. These results reveal that the modular nature of TGMs has allowed the fine tuning of the binding affinities of the T{beta}R- and co-receptor binding domains to establish cell specificity for TGF-{beta} signalling in a manner that cannot be attained by the mammalian cytokine.

immunology↗

bioRxiv2023

Wolbachia effects on thermal preference of natural Drosophila melanogaster are influenced by host genetic background, Wolbachia type and bacterial titer.

Temperature plays a fundamental role for the fitness of all organisms. In particular, it strongly affects metabolism and reproduction in ectotherms that have limited physiological capabilities to regulate their body temperature. Ectotherms thus have to maintain thermal homeostasis by behavioral adjustments. The influence of temperature variation on the physiology and behavior of ectotherms is well studied but we still know little about the influence of symbiotic interactions on thermal preference (Tp) of the host. The Wolbachia-Drosophila host-symbiont system represents an ideal model for addressing these questions. A growing number of studies demonstrated that different Wolbachia types can influence Tp in different Drosophila species, but these results may be confounded by the use of long-term Drosophila lab-strains that may not be representative for natural fly populations. To account for this, we investigated the effect of Wolbachia on Tp in wild-type D. melanogaster flies recently collected from nature. Consistent with previous data, we found reduced Tp compared to an uninfected control in one of two fly strains infected with the wMelCS Wolbachia type. Additionally, we, for the first time, found that Wolbachia titer variation influences thermal preference of the host fly. These data indicate that the interaction of Wolbachia and Drosophila resulting in behavioral variation is complex and strongly influenced by the genetic background of host and symbiont. Our results further emphasize the necessity for more in-depth studies to better understand the evolutionary significance of Tp variation influenced by Wolbachia in natural Drosophila populations.

ecology↗

bioRxiv2023

Wolbachia has no effect on thermal preference at different life-stages in highly inbred Drosophila melanogaster

Temperature fluctuations are challenging for ectotherms which are not able to regulate body temperature by physiological means and thus have to adjust their thermal environment via behavior. However, little is yet known about whether microbial symbionts influence thermal preference (Tp) in ectotherms by modulating their physiology. Several recent studies have demonstrated substantial effects of Wolbachia infections on host Tp in different Drosophila species. These data indicate that the direction and strength of thermal preference variation is strongly dependent on host and symbiont genotypes and highly variable among studies. By employing highly controlled experiments, we investigated the impact of several environmental factors including humidity, food quality, light exposure, and experimental setup that may influence Tp measurements in adult Drosophila melanogaster flies. Additionally, we assessed the effects of Wolbachia infection on Tp of Drosophila at different developmental stages, which has not been done before. We find only subtle effects of Wolbachia on host Tp which are strongly affected by experimental variation in adult, but not during juvenile life stages. Our in-depth analyses show that environmental variation has a substantial influence on Tp which demonstrates the necessity of careful experimental design and cautious interpretations of Tp measurements together with a thorough description of the methods and equipment used to conduct behavioral studies.

animal behavior and cognition↗

bioRxiv2020

A novel transcriptional signalling pathway mediated by the trafficking protein Ambra1 via scaffolding Atf2 complexes

Previously, we reported that Ambra1 is a core component of a cytoplasmic trafficking network, acting as a spatial rheostat to control active Src and FAK levels in addition to its critical roles in autophagy during neurogenesis. Here we identify a novel nuclear scaffolding function for Ambra1 that controls gene expression. Ambra1 binds to nuclear pore proteins, to other adaptor proteins like FAK and Akap8 in the nucleus, as well as to chromatin modifiers and transcriptional regulators such as Brg1, Cdk9 and the cAMP-regulated transcription factor Atf2. Ambra1 contributes to their association with chromatin and we identified genes whose transcription is regulated by Ambra1 complexes, likely via histone modifications and phospho-Atf2-dependent transcription. Therefore, Ambra1 scaffolds protein complexes at chromatin, regulating transcriptional signalling in the nucleus; in particular, it recruits chromatin modifiers and transcriptional regulators to control expression of genes such as angpt1, tgfb2, tgfb3, itga8 and itgb7 that likely contribute to the role of Ambra1 in cancer cell invasion.

cell biology↗