Kola-Ilesanmi, D. | bioRxiv Science

bioRxiv2026

BAG6 and RNF126 promote the degradation of cytosolic misfolded proteins that contain buried degron motifs

Missense mutations account for the majority of catalogued human disease-associated variants, and many are predicted to destabilize proteins and promote their degradation. To characterize the pathways responsible for recognizing and clearing such variants, we employed a two-pronged approach to identify both quality control components mediating turnover of misfolded proteins and the sequence elements within their substrates that drive this process. Using a panel of unstable cytosolic missense variants in proximity-labeling and RNAi-based experiments, we identified the BAG6-RNF126 pathway as contributing to the clearance of a subset of these substrates. Applying a tile-based approach to a model cytosolic protein, we uncovered strong potential degrons, including a C-terminal degron degraded in part in a BAG6- and RNF126-dependent manner. Modeling supports that this degron can be accommodated by BAG6. Together, our findings add to the growing body of evidence implicating the BAG6-RNF126 pathway as a key mediator of cytosolic protein quality control.

molecular biology↗

bioRxiv2024

Beta-cell adaptation to metabolic stresses requires prolactin receptor signaling

The role of prolactin receptor (PRLR) signaling in {beta}-cell adaptation to maternal insulin resistance of pregnancy has been well demonstrated. Using transgenic mice with an inducible {beta}-cell-specific Prlr deletion ({beta}Prlr-/-), we found that intact PRLR, as found in {beta}Prlr+/+ mice, were protected from developing glucose intolerance during pregnancy, and the main mechanism responsible for this PRLR-mediated effect is the up regulation of {beta}-cell proliferation and insulin synthesis. Interestingly, studies in male mice and humans have found a link between diminished PRLR signaling and abnormal {beta}-cell function. We aimed to determine whether PRLR has a role in regulating {beta}-cell function outside of pregnancy, protecting {beta}-cell against exposure to metabolic stressors. In this study, we found that {beta}-cell-specific PRLR reduction resulted in impaired glucose tolerance in multiparous female mice challenged with a 12-week course of high-fat diet (HFD). Unlike in pregnancy, where PRLR signaling up regulates {beta}-cell proliferation resulting in a greater {beta}-cell mass, we observed no difference in {beta}-cell mass between the wild type ({beta}Prlr+/+) and mutant ({beta}Prlr-/-) mice. In vitro glucose-stimulated insulin secretion using isolated islets from wild type ({beta}Prlr+/+) and mutant ({beta}Prlr-/-) mice showed comparable insulin response, but {beta}Prlr-/- mice showed blunted first-phase insulin release in vivo, although only when challenged with glucose orally and not intraperitoneally, suggesting an impairment of the incretin effect. In support of the observed defect in incretin action, we found a reduction in expression of both incretin hormone receptors, Gipr and Glp-1r, and several of their upstream regulators, such as E2f1, Nkx6.1, Pax6, Ppar{gamma}, and Tcf7l2. Islets from the mutant mice also have a lower insulin content and reduced levels of genes that regulate glucose metabolism. Together, these results suggested that PRLR signaling plays an important role in preserving {beta}-cell function in mice exposed to metabolic stress by maintaining incretin receptor expression and insulin secretory capacity in {beta} cells.

physiology↗