CRM1 is a highly conserved, RanGTPase-driven exportin that carries proteins and RNPs from the nucleus to the cytoplasm. We now explored the cargo-spectrum of CRM1 in depth and identified surprisingly large numbers, namely >700 export substrates from the yeast S. cerevisiae, ≈1000 from Xenopus oocytes and >1050 from human cells. In addition, we quantified the partitioning of ≈5000 unique proteins between nucleus and cytoplasm of Xenopus oocytes. The data suggest new CRM1 functions in spatial control of vesicle coat-assembly, centrosomes, autophagy, peroxisome biogenesis, cytoskeleton, ribosome maturation, translation, mRNA degradation, and more generally in precluding a potentially detrimental action of cytoplasmic pathways within the nuclear interior. There are also numerous new instances where CRM1 appears to act in regulatory circuits. Altogether, our dataset allows unprecedented insights into the nucleocytoplasmic organisation of eukaryotic cells, into the contributions of an exceedingly promiscuous exportin and it provides a new basis for NES prediction.Animals, plants and other eukaryotic organisms subdivide their cells into compartments that carry out specific tasks. For example, the cell nucleus hosts the genome and handles the genetic information, whereas the surrounding cytoplasm is specialized in making proteins. These proteins are then either used in the cytoplasm or transported to the nucleus and other cell compartments. Since proteins are not made in the nucleus, all proteins in this compartment must be imported from the cytoplasm.Two layers of membrane separate the nucleus and cytoplasm from each other. Any exchange of material must therefore proceed through channels called nuclear pore complexes, or NPCs for short. The NPCs have filters that allow only small molecules a free transit, while larger ones are typically rejected. However, larger proteins may also rapidly pass through the nuclear pore complexes if loaded onto dedicated shuttle molecules; for example, “exportins” transport proteins out of the nucleus.Kırlı, Karaca et al. used an approach called proteomics to measure the levels of 5,000 different proteins within the nucleus and the cytoplasm. Such a census helps to predict where a given protein works and where it might cause problems. Further experiments also used proteomics to identify which proteins are carried by an exportin called CRM1. This revealed that a remarkably large number of different proteins (around 1,000) are exported by CRM1 from either yeast, human or frog cell nuclei. Most of these “cargo” proteins were previously thought to never leave the cytoplasm. It now seems, however, that these proteins can leak into the nucleus, but CRM1 recognizes them as cytoplasmic proteins and expels them from the nucleus.These findings suggest that the border control at NPCs is less perfect than was previously believed. If not remedied, this would pose a serious problem for the cell, because the accumulation of "wrong" proteins inside the nucleus would disturb the processes that occur there and could destabilize the genome. Kırlı, Karaca et al. propose that the export of such accidentally displaced proteins by CRM1 is a crucial measure to protect the nucleus.
Kırlı, K., Karaca, S., Dehne, H. J., Samwer, M., Pan, K. T., Lenz, C., … Görlich, D. (2015). A deep proteomics perspective on CRM1-mediated nuclear export and nucleocytoplasmic partitioning. ELife, 4. https://doi.org/10.7554/elife.11466