Biology subjects

von Eyss, B.

Publications and source records attributed to von Eyss, B..

4 recordsLinked to original sources

bioRxiv2023

A YIPF5-GOT1A/B complex directs a transcription independent function of ATF6 in ER export

Exit from the endoplasmic reticulum is mediated by the Sar1/COPII machinery and a number of accessory factors. How the initial steps of cargo recruitment upstream of Sar1/COPII are mediated remains unclear, but the dihydropyridine FLI-06 inhibits cargo recruitment into ER exit sites. Here, we used chemical genetics screening approaches in conjunction with FLI-06 treatment and identified the ER membrane proteins YIPF5 and GOT1A/B as putative components of early export processes. Surprisingly, the two homologous proteins GOT1A and GOT1B, coded by GOLT1A and GOLT1B, respectively, exhibited opposite functions after treatment with FLI-06: increasing the expression of GOT1A or reducing the expression of GOT1B or YIPF5 prevented inhibition of ER-export by FLI-06. Inhibiting ER export with FLI-06 elicited a specific ER stress-related gene expression signature distinct from the ER-stress signature induced by Thapsigargin. The interactomes of GOT1A and GOT1B suggested a connection to ER-stress mediators. Moreover, RNA-Seq data showed that FLI-06-induced genes are strongly enriched for ATF6 target genes which are suppressed by GOLT1A overexpression or GOLT1B knock-down. This suggests that ATF6 signaling is involved in FLI-06-mediated toxicity, and we could demonstrate that siRNA-mediated knock-down or specific inhibitor of ATF6 rescued cells from FLI-06-mediated cell death. Knock-down or inhibition of ATF6 is sufficient to resume transport from the ER under FLI-06-treatment, suggesting that ATF6 is directly involved in the FLI-06-mediated ER-export block. Surprisingly, our data show that this ATF6 function is independent of de novo transcription, implying a novel, transcription-independent function of ATF6.

cell biology↗

bioRxiv2023

TRPS1 maintains luminal progenitors in the mammary gland by repressing SRF/MRTF activity

The transcription factor TRPS1 is a context-dependent oncogene in breast cancer [1] [2] [3] [4] [5]. In the mammary gland, TRPS1 activity is restricted to the luminal population and is critical during puberty and pregnancy [2]. Its function in the resting state remains however unclear. To evaluate whether it could be a target for cancer therapy, we investigated TRPS1 function in the healthy adult mammary gland using a conditional ubiquitous depletion mouse model where long-term depletion does not affect fitness. We show that TRPS1 activity is essential to maintain a functional luminal progenitor compartment. This requires the repression of both YAP/TAZ and SRF/MRTF activities, TRPS1 represses SRF/MRTF activity indirectly by modulating RhoA activity. Our work uncovers a hitherto undisclosed function of TRPS1 in luminal progenitors intrinsically linked to mechanotransduction in the mammary gland. It also provides new insights into the oncogenic functions of TRPS1 as luminal progenitors are likely the cells of origin of many breast cancers. Significance statementThe transcription factor TRPS1 is a context-dependent oncogene in breast cancer. It is unclear how TRPS1 contributes to cancer development and whether it could be a target for therapy. Here we established a mouse model mimicking the systemic effect of TRPS1 drug targeting. With this model, we can show that TRPS1 depletion does not impact the fitness of the animals and that the role of TRPS1 is to maintain a functional luminal progenitor pool in the mammary gland. Mechanistically, TRPS1 represses a mechano-transduction program preventing their commitment to an alveolar fate. Because there is growing evidence that breast cancer originates from the expansion of altered luminal progenitors, our work provides valuable insights into the understanding of breast cancer initiation.

cell biology↗

bioRxiv2023

A noncanonical repressor function of JUN restrains YAP activity and suppresses YAP-dependent liver cancer growth

Yes-associated protein (YAP) and its homologue, transcriptional coactivator with PDZ-binding motif (TAZ), are the main transcriptional downstream effector of the Hippo pathway. Decreased Hippo pathway activity leads to nuclear translocation of YAP/TAZ where they interact with TEAD transcription factors to induce target gene expression. Unrestrained YAP/TAZ activity can lead to excessive growth and tumor formation in a short time, underscoring the evolutionary need for tight control of these two transcriptional coactivators. The AP-1 complex binds together with YAP/TAZ to many common sites and they form a positive feed-forward to induce gene expression. Here, we report that the AP-1 component c-JUN acts as specific repressor of YAP/TAZ at joint target sites to decrease YAP/TAZ activity. This function of c-JUN is independent of its heterodimeric AP-1 partner c-FOS demonstrating that it is independent of the canonical AP-1 function to induce target gene expression. Since c-JUN is itself by YAP/TAZ, our work identifies a negative feedback loop that buffers YAP/TAZ activity at joint sites. This negative feedback loop needs to get disrupted in liver cancer to unlock the full oncogenic potential of YAP/TAZ. Our results thus demonstrate an additional layer of control for the important interplay of YAP/TAZ and AP-1.

molecular biology↗

bioRxiv2023

Inhibition of YAP the MMB interaction and targeting NEK2 as potential therapeutic strategies for YAP-driven cancers

YAP activation in cancer is linked to poor outcomes, making it an attractive therapeutic target. Previous research focused on blocking the interaction of YAP with TEAD transcription factors. Here, we took a different approach by disrupting YAPs binding to the transcription factor B-MYB using MY-COMP, a fragment of B-MYB containing the YAP binding domain fused to a nuclear localization signal. MY-COMP induced cell cycle defects, nuclear abnormalities, and polyploidization. In an AKT and YAP-driven liver cancer model, MY-COMP significantly reduced liver tumorigenesis, highlighting the importance of the YAP-B-MYB interaction in tumor development. MY-COMP also perturbed the cell cycle progression of YAP-dependent uveal melanoma cells but not of YAP-independent cutaneous melanoma cell lines. It counteracted YAP-dependent expression of MMB-regulated cell cycle genes, explaining the observed effects. We also identified NIMA-related kinase (NEK2) as a downstream target of YAP and B-MYB, promoting YAP-driven transformation by facilitating centrosome clustering and inhibiting multipolar mitosis.

cancer biology↗