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Abstract Nucleocytoplasmatic transport plays an essential role in eukaryotic cell homeostasis and is mediated by karyopherins. Importin β1 (KPNB1) and its adaptor protein importin α1 (KPNA2) are the best-characterized karyopherins that effect nuclear import. Here, we identify a novel small-molecule inhibitor of the importin β1-mediated nuclear import. We design a reporter cell line by stably tagging endogenous importin α1 with a fluorescent protein to screen for compounds affecting its subcellular localization. We identify a series of compounds that trigger cytoplasmatic accumulation of importin α1. The lead compound, ibetazol, is further characterized in a broad sequence of cellular nuclear transport assays. Ibetazol is shown to inhibit all importin β1-mediated nuclear import quickly and specifically, without affecting transport mediated by other karyopherins. Detailed molecular mechanism of action studies demonstrate that ibetazol inhibits importin β1 by covalently targeting Cys585. In summary, ibetazol is a novel small molecule inhibitor of importin β1 enabling pharmacological inhibition of the importin β1-mediated nuclear import process with wide applicability in different fields.

Abstract A spontaneously occurring temperature increase in solid tumors has been reported sporadically, but is largely overlooked in terms of cancer biology. Here we show that temperature is increased in tumors of patients with pancreatic ductal adenocarcinoma (PDAC) and explore how this could affect therapy response. By mimicking this observation in PDAC cell lines, we demonstrate that through adaptive changes in lipid metabolism, the temperature increase found in human PDAC confers protection to lipid peroxidation and contributes to gemcitabine resistance. Consistent with the recently uncovered role of p38 MAPK in ferroptotic cell death, we find that the reduction in lipid peroxidation potential following adaptation to tumoral temperature allows for p38 MAPK inhibition, conferring chemoresistance. As an increase in tumoral temperature is observed in several other tumor types, our findings warrant taking tumoral temperature into account in subsequent studies related to ferroptosis and therapy resistance. More broadly, our findings indicate that tumoral temperature affects cancer biology.

“Intracellular phase separation is emerging as a universal principle for organizing biochemical reactions in time and space. Here the authors show that PopZ condensate dynamics support cell division and using PopZ modular architecture, the tunable PopTag platform was developed to enable designer condensates.”

Cancer therapy drugs are designed to target genetic vulnerabilities, but loss-of-function screens often fail to identify essential genes in drug mechanism studies. Here the authors demonstrate CRISPRres, which exploits in-frame variation generated by indel formation to discover gene-drug interactions.