Nuclear envelope budding is a response to cellular stress

Nuclear envelope budding (NEB) is a recently discovered alternative pathway for nucleocytoplasmic communication distinct from the movement of material through the nuclear pore complex. Through quantitative electron microscopy and tomography, we demonstrate how NEB is evolutionarily conserved from early protists to human cells. In the yeast Saccharomyces cerevisiae, NEB events occur with higher frequency during heat shock, upon exposure to arsenite or hydrogen peroxide, and when the proteasome is inhibited. Yeast cells treated with azetidine-2-carboxylic acid, a proline analogue that induces protein misfolding, display the most dramatic increase in NEB, suggesting a causal link to protein quality control. This link was further supported by both localization of ubiquitin and Hsp104 to protein aggregates and NEB events, and the evolution of these structures during heat shock. We hypothesize that NEB is part of normal cellular physiology in a vast range of species and that in S. cerevisiae NEB comprises a stress response aiding the transport of protein aggregates across the nuclear envelope. Significance StatementA defining feature of eukaryotes is the nuclear envelope, a double lipid bilayer that serves to isolate and protect the cells genetic material. Transport of large molecules over this barrier is believed to occur almost exclusively via the nuclear pores. However, herpes virions and mega ribonucleoproteins (megaRNPs) use an alternative means of transport - via nuclear envelope budding (NEB). Here, we show NEB is a ubiquitous eukaryotic phenomenon and increases when exposed to various forms of cellular stress. NEB frequency was maximal when the cell was challenged with a drug that induces protein misfolding, indicating this transport pathway plays a role in protein quality control. These results imply that NEB is an underappreciated yet potentiallyfundamental means of nuclear transport.