Assrir, N. | bioRxiv Science

bioRxiv2026

Cytoplasmic FKBP7 reflux controls NFE2L1 levels as an adaptive response to chemotherapy in prostate cancer cells

Understanding how cancer cells adapt to chemotherapy is essential for overcoming resistance. One mechanism involved in taxane resistance in prostate cancer is mediated by FKBP7, a still-understudied endoplasmic reticulum-resident cis-trans isomerase. Using cell fractionation, we demonstrate that the ERAD-independent retrotranslocation of FKBP7 into the cytosol correlates with the oxidative stress triggered by chemotherapy, as an escape response. Once in the cytosol, FKBP7 interacts with the translation machinery and with eIF4G1, specifically with its C-terminal HEAT3 domain. Following FKBP7 silencing, polysome profiling and RNA sequencing identified the transcription factor NFE2L1 - a key regulator of oxidative stress adaptation - as an effector of FKBP7. Here, we also produced the first NMR spectra of the FKBP7 catalytic domain, revealing a well-folded protein that binds to rapamycin and everolimus but not to FK506. Overall, our results demonstrate that chemotherapy-induced oxidative stress triggers an adaptive mechanism in which FKBP7 is translocated into the cytosol where it modulates NFE2L1, thereby enabling the survival of resistant cells. These findings lead us to propose the targeting of FKBP7/NFE2L1 signaling as a strategy to overcome adaptive resistance.

cancer biology↗

bioRxiv2020

Structural and dynamic characterization of the C-terminal tail of ErbB2: disordered but not random

ErbB2 (or HER2) is a receptor tyrosine kinase overexpressed in some breast cancers, associated with poor prognosis. Treatments targeting the receptor extracellular and kinase domains have greatly improved disease outcome in the last twenty years. In parallel, the structures of these domains have been described, enabling better mechanistic understanding of the receptor function and targeted inhibition. However, ErbB2 disordered C-terminal cytoplasmic tail (CtErbB2) remains very poorly characterized in terms of structure, dynamics and detailed functional mechanism. Yet, it is where signal transduction is triggered, via phosphorylation of tyrosine residues, and carried out, via interaction with adaptor proteins. Here we report the first description of ErbB2 disordered tail at atomic resolution, using NMR and SAXS. We show that although no part of CtErbB2 has any stable secondary or tertiary structure, it has around 20% propensity for a N-terminal helix that is suspected to interact with the kinase domain, and many PPII stretches distributed all along the sequence, forming potential SH3 and WW domains binding sites. Moreover, we identified a long-range transient contact involving CtErbB2 termini. These characteristics suggest new potential mechanisms of auto-regulation and protein-protein interaction. SIGNIFICANCEWe report here the first description of the receptor tyrosine kinase ErbB2 disordered tail (CtErbB2) at atomic resolution, using NMR and SAXS. We show that although CtErbB2 exhibits no stable structure, it does exhibit partial secondary and tertiary structures likely important for its function. These structural elements are consistent with an active role of the C-terminal tail in the regulation of the receptors activity, thanks to the presence of preformed structures for intramolecular interactions, as well as long-range contacts modulating accessibility of those sites and proline interaction sites distinct from the main tyrosine sites. Together, those results reinforce the view that disordered tails of receptors are more than random anchors for partners.

biophysics↗