Traffic control at the nuclear pore.

The proper communication between organelles is essential for many aspects of eukaryotic life. The coordination of nuclear and cytoplasmic activities in particular is of pivotal importance and depends on transport in and out of the nucleus. The material which translocates through nuclear pores is diverse; it includes numerous proteins, RNAs and large ribonucleoprotein complexes like ribosomal subunits. To ensure the correct nucleocytoplasmic distribution of these components, appropriate mechanisms have to be in place which control traffic across the nuclear envelope. A growing number of studies support the notion that transport through nuclear pore complexes is intimately linked to cell physiology. As such, it has become evident that changes in the cellular environment, either by externally applied stress, aging or disease, alter nuclear traffic. Due to the progress made in the past few years, we are now beginning to understand these processes at the molecular level. Thus, the concept emerges that stress or disease conditions correlate with signaling events which aim at the nuclear transport apparatus. Here, we summarize results from recent publications that provide evidence for the hypothesis that changes in cell physiology modulate nuclear traffic by targeting multiple transport factors. We propose that this traffic control is at least in part mediated by specific signaling events.

Oxidative stress inhibits nuclear protein export by multiple mechanisms that target FG nucleoporins and Crm1.

Nuclear transport of macromolecules is regulated by the physiological state of the cell and thus sensitive to stress. To define the molecular mechanisms that control nuclear export upon stress, cells were exposed to nonlethal concentrations of the oxidant diethyl maleate (DEM). These stress conditions inhibited chromosome region maintenance-1 (Crm1)-dependent nuclear export and increased the association between Crm1 and Ran. In addition, we identified several repeat-containing nucleoporins implicated in nuclear export as targets of oxidative stress. As such, DEM treatment reduced Nup358 levels at the nuclear envelope and redistributed Nup98. Furthermore, oxidative stress led to an increase in the apparent molecular masses of Nup98, Nup214, and Nup62. Incubation with phosphatase or beta-N-acetyl-hexosaminidase showed that oxidative stress caused the phosphorylation of Nup98, Nup62, and Nup214 as well as O-linked N-acetylglucosamine modification of Nup62 and Nup214. These oxidant-induced changes in nucleoporin modification correlated first with the increased binding of Nup62 to the exporter Crm1 and second with the reduced interaction of Nup62 with other FxFG-containing nucleoporins. Together, oxidative stress up-regulated the binding of Crm1 to Ran and affected multiple repeat-containing nucleoporins by changing their localization, phosphorylation, O-glycosylation, or interaction with other transport components. We propose that the combination of these events contributes to the stress-dependent regulation of Crm1-mediated protein export.