Premature aging disorders provide an opportunity to study the mechanisms that drive aging. In Hutchinson-Gilford progeria syndrome (HGPS), a mutant form of the nuclear scaffold protein lamin A distorts nuclei and sequesters nuclear proteins. We sought to investigate protein homeostasis in this disease. Here, we report a widespread increase in protein turnover in HGPS-derived cells compared to normal cells. We determine that global protein synthesis is elevated as a consequence of activated nucleoli and enhanced ribosome biogenesis in HGPS-derived fibroblasts. Depleting normal lamin A or inducing mutant lamin A expression are each sufficient to drive nucleolar expansion. We further show that nucleolar size correlates with donor age in primary fibroblasts derived from healthy individuals and that ribosomal RNA production increases with age, indicating that nucleolar size and activity can serve as aging biomarkers. While limiting ribosome biogenesis extends lifespan in several systems, we show that increased ribosome biogenesis and activity are a hallmark of premature aging.

The genome is packaged and organized nonrandomly within the 3D space of the nucleus to promote efficient gene expression and to faithfully maintain silencing of heterochromatin. The genome is enclosed within the nucleus by the nuclear envelope membrane, which contains a set of proteins that actively participate in chromatin organization and gene regulation. Technological advances are providing views of genome organization at unprecedented resolution and are beginning to reveal the ways that cells co-opt the structures of the nuclear periphery for nuclear organization and gene regulation. These genome regulatory roles of proteins of the nuclear periphery have important influences on development, disease and ageing.

The RGS7 (R7) family of G protein regulators, G␤5, and R7BP form heterotrimeric complexes that potently regulate the kinetics of G protein-coupled receptor signaling. Reversible palmitoylation of R7BP regulates plasma membrane/nuclear shuttling of R7⅐G␤5⅐R7BP heterotrimers. Here we have investigated mechanisms whereby R7BP controls the function of the R7 family. We show that unpalmitoylated R7BP undergoes nuclear/cytoplasmic shuttling and that a C-terminal polybasic motif proximal to the palmitoylation acceptor sites of R7BP mediates nuclear localization, palmitoylation, and plasma membrane targeting. These results suggest a novel mechanism whereby palmitoyltransferases and nuclear import receptors both utilize the C-terminal domain of R7BP to determine the trafficking fate of R7⅐G␤5⅐R7BP heterotrimers. Analogous mechanisms may regulate other signaling proteins whose distribution between the plasma membrane and nucleus is controlled by palmitoylation. Lastly, we show that cytoplasmic RGS7⅐G␤5⅐R7BP heterotrimers and RGS7⅐G␤5 heterodimers are equivalently inefficient regulators of G proteincoupled receptor signaling relative to plasma membrane-bound heterotrimers bearing palmitoylated R7BP. Therefore, R7BP augments the function of the complex by a palmitoylation-regulated plasma membrane-targeting mechanism. G protein-coupled receptor (GPCR)3 signal transduction regulates a wide variety of physiological processes. For example in the nervous system, dopamine, serotonin, acetylcholine, and norepinephrine activate presynaptic GPCRs that regulate glutamate or ␥-aminobutyric acid release. GPCRs transduce signals via G protein-dependent and -independent mechanisms (reviewed in Refs. 1-3). GPCR signaling via heterotrimeric G proteins regulates second messenger production and ion channel activity (1-3), whereas G protein-independent signaling can activate mitogen-activated protein kinase pathways (4), nonreceptor tyrosine kinases (5, 6), and phosphatidylinositol 3-phosphate kinase (7,8). GPCR signaling from the plasma membrane to the nucleus may also occur by nuclear shuttling of ␤-arrestin 1 (9 -11).GPCR signaling is regulated potently by the RGS (regulator of G protein signaling protein) protein family (reviewed in Ref. 12). RGS proteins regulate the kinetics and amplitude of GPCR signaling by acting as GTPase-activating proteins (GAPs) for G␣ subunits (13-15). Certain RGS proteins also function as G␣ effectors or antagonists (reviewed in Ref. 12).Members of the RGS7 (R7) subfamily of RGS proteins (RGS6, RGS7, RGS9-1, RGS9-2, and RGS11) are of particular interest because of their biologic importance and unusual subunit structures. R7 family members are highly expressed in the visual and nervous systems (16 -19). They selectively deactivate G␣ subunits of the G i/o family (20 -22) that mediate phototransduction and the effects of modulatory neurotransmitters (reviewed in Ref. 23). Best understood is RGS9, which regulates GPCR signaling in the basal ganglia (24 -27) and phototransduction in retina (28). In contrast to oth...

Nup50 is a mobile nucleoporin with a pronounced presence both at the nuclear pore complex and in the nucleoplasm that can move between these different localizations. The dynamic behavior of Nup50 in both locations is dependent on active transcription by RNA polymerase II.