Biology subjects

Hiltunen, J.

Publications and source records attributed to Hiltunen, J..

3 recordsLinked to original sources

bioRxiv2026

MauE from Calditrichota and Thermodesulfobacteriota reveal a new pathway for disulfide bond formation in bacteria

Disulfide bond formation is crucial to the structure and function of many proteins. It is known that there is diversity in the pathways for disulfide bond formation in bacteria and that there are gaps in our knowledge of these pathways. Using a combination of experimental and bioinformatic approaches we show that some of these gaps can be filled by a newly discovered oxidative folding pathway centered on methylamine utilization protein E (MauE). MauE has previously been associated with the methylamine utilization (MAU) gene cluster, which is involved in methylamine metabolism, in particular it is associated with the maturation of the small subunit of methylamine dehydrogenase. Here we show MauE from Caldithrix abyssi and Desulfatibacillum alphaticivorans functionally replace disulfide bond formation protein B (DsbB) in E. coli using two independent disulfide bond dependent assays. Furthermore, MauE is found in 14 species from 2 bacterial phyla that lack known pathways for structural disulfide bond formation, but which have proteins with structural disulfide bonds in the protein data bank. The active site for MauE was determined to be a conserved CXC motif. Using molecular docking predictions, we demonstrate that MauE is likely to interact with ubiquinone, similarly to the well characterized bacterial DsbB. We also constructed a dataset across thirty-five different phyla to demonstrate that MauE is potentially the second most common disulfide bond formation protein in bacterial disulfide bond formation pathways after DsbB. In addition, the distribution of MauE largely differs from the distribution of other MAU gene cluster markers affirming its role as a newly discovered generalist disulfide bond formation protein rather than being a specialized maturation factor for methylamine dehydrogenase. We also reveal further gaps in disulfide bond pathways, as well as species which may contain redundancies in their disulfide bond pathways.

biochemistry↗

bioRxiv2025

p63-GATA2 molecular switch mediates the tumor suppressor to oncogene transition of glucocorticoid receptor in the prostate

Glucocorticoids are widely used to alleviate inflammation and treatment-related side effects in prostate cancer (PCa), particularly to counteract abiraterone-induced cortisol suppression. However, the glucocorticoid receptor (GR) exhibits a dual role exerting tumor-suppressive effects by inhibiting early-stage PCa cell proliferation, while also promoting oncogenic progression by mediating antiandrogen resistance. The molecular mechanisms underlying this functional dichotomy have remained elusive and poorly characterized. Using genome-wide analyses and CRISPR-based genome editing, we identified the tumor protein p63 as a key mediator of GRs tumor-suppressive chromatin activity and maintenance of basal epithelial cell identity. Loss of p63 reprograms GR activity toward an oncogenic state, marked by basal-to-luminal transition, enhanced cell migration, invasion, and altered morphology accompanied by increased epithelial-mesenchymal transition markers. This functional shift is driven by elevated expression of transcription factors GATA2 and FRA1, which remodel GRs chromatin binding and transcriptional output to activate oncogenic signaling pathways. Together, our findings uncover a molecular switch that governs the dual role of GR in PCa, establishing transcription factor crosstalk as a critical regulator of GR-driven oncogenic reprogramming and cellular plasticity. These findings establish a framework for understanding glucocorticoid-induced tumor suppression and highlight GATA2 and FRA1 as potential targets to mitigate GR-mediated resistance in PCa.

genomics↗

bioRxiv2024

Steroid receptor-assisted loading modulates transcriptional responses in prostate cancer cells

Steroid receptors are involved in a wide array of crosstalk mechanisms that regulate diverse biological processes, with significant implications in diseases, particularly in cancers. In prostate cancer, indirect crosstalk between androgen receptor (AR) and glucocorticoid receptor (GR) is well-documented, wherein AR suppression by antiandrogen therapy leads to elevated GR levels, enabling GR to compensate for and replace AR signaling. However, the existence and impact of direct chromatin crosstalk between AR and GR in prostate cancer have remained elusive. Our genome-wide investigations reveal that AR activation significantly expands GR chromatin binding. Mechanistically, AR induces remodeling of closed chromatin sites, facilitating GR binding to inaccessible sites. Importantly, coactivation of AR and GR results in distinct transcriptional responses at both the cell population and single-cell levels. Intriguingly, pathways affected by these transcriptional changes are generally associated with improved patient survival. Thus, the direct crosstalk between AR and GR yields markedly different outcomes from the known role of GR in circumventing AR blockade by antiandrogens.

genomics↗