Adding complexity to the nuclear pore complex

Nuclear pore complexes (NPCs) span the inner and outer membranes of the nuclear envelope and mediate transport between the nucleus and cytoplasm. In recent years, however, NPCs and the proteins that form them, known as nucleoporins, have also been linked to nuclear events including chromatin organization and gene expression , and to physiological processes such as differentiation and aging. Two papers now define the function of individual nucleoporins in mouse muscle differentiation (1) and budding yeast lifespan (2). NPCs are composed of ‫03ف‬ different nucleoporins. In 2012, Martin Hetzer and colleagues at the Salk Institute in La Jolla, California, discovered that one particular nucleoporin, gp210/Nup210, is required for both neuronal and muscle differentiation. Myoblasts lacking Nup210, for example, undergo apoptosis instead of fusing together to form multinucleate myotubes (3). To investigate how gp210/Nup210 promotes muscle differentiation, Hetzer and his graduate student Sebastian Gomez-Cavazos fi rst determined which parts of the protein were required for myoblast fusion (1). Nup210 is a large transmembrane protein with a small C-terminal region facing the NPC, and a large, well-conserved N-terminal domain that protrudes into the peri-nuclear space between the inner and outer nuclear membranes. Nup210 mutants lacking the luminal domain failed to promote myo-blast differentiation, whereas a version of the protein lacking the C-terminal domain supported myo-tube formation, even though it no longer localized effi ciently to NPCs. " We wondered then whether Nup210 was acting away from nuclear pores, " Hetzer says. Indeed, Nup210 mutants completely unable to localize to NPCs still supported muscle differentiation as long as the protein's N-terminal luminal domain was retained in the perinuclear space, which is continuous with the ER lumen. But what does Nup210's luminal domain do to promote myotube formation? Muscle differentiation normally activates a mild stress response in the ER that helps to maintain calcium homeostasis and protein folding. Too much stress, however, can induce an ER-specifi c caspase cascade that triggers cell death. Gomez-Cavazos and Hetzer found that the ER stress response was highly activated in gp210/Nup210-defi cient myoblasts undergoing differentiation. Inhibiting the ER stress-specifi c caspase cascade blocked cell death and restored the cells' ability to form differentiated myotubes. Nup210's luminal domain therefore appears to help muscle cells tolerate stressful conditions within the ER lumen/perinuclear space throughout differentiation. " It might be involved in calcium homeosta-sis, or it could act as a protein chaperone, " Hetzer speculates. interested in following up on a …