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Interestingly, there are mechanistic links between nucleolar stress and autophagy Pfisterand nucleolar proteins /3124.txt be degraded via nucleophagy Mostofa et al. Lipid droplets can serve as an intermediary organelle for ERAD where cargo bound for degradation transit on the lipid droplet surface before being degraded by the freee Olzmann and Carvalho Saddles Seatpost Laapierre Seatposts. Lapierre x control 2018 free recognize nuclear localization sequences of cytoplasmic proteins and mediate their transit from cytoplasm to nucleus. The hallmarks of aging. Copy Download.
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Browse other Mountain Bikes Free shipping and free day returns on all U. Browse other Mountain Bikes. From synthesis to degradation, proteins are constantly surveilled for proper folding and damage, but their dynamic subcellular partitioning, preponderance in different compartments, and association with various organelles leads to a variety of proteostatic outcomes that have important ramifications on disease onset and progression, and ultimately on aging itself.
Therefore, spatio-temporal regulation of proteostasis is key in somatic maintenance and health Sontag et al. This review highlights subcellular mechanisms of proteostasis and their impact on longevity and aging, with an emphasis on protein trafficking across the nuclear pore as well as specific nuclear and cytoplasmic proteostatic mechanisms.
Proteome partitioning between the cytoplasm and the nucleus is mediated by passive and facilitated transport of proteins across the nuclear pore Knockenhauer and Schwartz ; Timney et al. Altogether, the nuclear pore structure includes a ring-like pore, a nuclear basket, and cytoplasmic filaments Solmaz et al. Some of the nuclear pore proteins have particularly long lifespan in the nuclear pore and are exchanged at a low rate Toyama et al.
Indeed, with age, nuclear pore complex instability and permeability progressively increases, leading to mislocalization of several proteins, a phenomenon that is prevented in long-lived nematodes Doucet et al. Altogether, these studies suggest that maintenance of the nuclear pore integrity is essential for longevity Toyama and Hetzer The accepted passive threshold across the nuclear pore is 40 kDa Knockenhauer and Schwartz ; Schmidt and Gorlich and transporters called karyopherins can recognize and facilitate the traffic of larger proteins across the nuclear pore, a process involving Ran GTPases Cavazza and Vernos The karyopherin family of proteins consists of trafficking receptors named importins 18 in humans and exportins 6 in humans.
Importins recognize nuclear localization sequences of cytoplasmic proteins and mediate their transit from cytoplasm to nucleus. Exportins recognize nuclear export sequences of nuclear-localized proteins and facilitate their transport from the nucleus to the cytoplasm. To maintain transport capacities across the nuclear pore, karyopherins are returned to their relevant site of action after trafficking.
This dynamic cycle of import and export governs the temporal specification of nuclear and cytoplasmic proteomes, and ultimately impacts an array of key cellular processes including pathways associated with aging Fig. Several diseases have a fundamental basis in nucleocytoplasmic transport dysfunction, including cancer Gandhi et al. Many neurodegenerative diseases are characterized by impairments in nucleocytoplasmic protein partitioning Kim and Taylor and nucleolar dynamics White et al.
Since intracellular mislocalization of proteins can lead to deleterious compartmental loss-of-function s or predispose mislocalized cargo proteins to aggregate and impair proteostatic mechanisms, nuclear transport dysfunction may be a factor underling the onset of neurodegeneration Kim and Taylor In nuclei of cells from Hutchinson-Gilford progeria syndrome patients, mutated lamins that normally would provide structural support aberrantly accumulate, resulting in genomic instability, a feature exacerbated by dysfunctional nuclear protein transport Kelley et al.
Phosphorylated form of the protein Tau Bejanin et al. Studies of different proteinopathies have identified key importins and exportins as modifiers of the onset of these diseases Fig. This pre-import disaggregation function demonstrates that repartitioning of certain RNA-binding proteins from the cytosol to the nucleus may improve the solubility and function of proteins that are bound to aggregate and mediate proteotoxicity in the cytoplasm. In turn, this chaperone-like function likely reduces the proteostatic burden in the cytoplasm, in addition to refolding and compartmentalization of unstable proteins in order to restore their native structure and function.
Alternatively, unstable protein import in the nucleus may facilitate their degradation via nuclear 26S proteasomes Albert et al. XPO1 is a highly conserved nuclear export receptor involved in trafficking several proteins including translation factors, vesicle coat proteins, centrosomal and autophagy proteins, ubiquitin pathway proteins, and ribosomal subunits out of the nucleus Kirli et al. Notably, XPO1 levels are elevated in various cancers leading to nuclear depletion of tumor-suppressing proteins Gandhi et al.
Recently developed XPO1 inhibitors showed success in slowing tumorigenesis in a variety of cancers and the selective inhibitor of nuclear export SINE , Selinexor KPT, Karyopharm Therapeutics , was approved for relapsed multiple myelomas in Chen et al.
Inhibition of XPO1 using SINE leads to nucleocytoplasmic repartitioning of several proteins and a corresponding reduction in translation rate Wahba et al. This is associated with improvement in the process of autophagy and lysosomal biogenesis via the nuclear enrichment of the autophagy transcriptional regulator TFEB Silvestrini et al.
XPO1 inhibition was also recently shown to mitigate the nuclear defects of progeria Garcia-Aguirre et al. Overall, the dynamics of nucleocytoplasmic protein partitioning is an emerging field with promising potential to markedly enhance our understanding of the process of aging and the onset of age-related diseases. Moreover, the development of new selective inhibitors of karyopherins is bound to improve our ability to pharmacologically modify the partitioning of proteins in cells in order to modulate proteostasis by leveraging different proteostatic mechanisms in the nucleus and the cytoplasm.
The nuclear proteome is diverse and requires proper protein surveillance in order to maintain nuclear structure and dynamic processes that characterize this essential organelle Enam et al. As cellular proteome is specified by ribosomes, proper assembly of pre-ribosome subunits in the nucleus ultimately governs the rate of mRNA translation. Ribosome assembly originates inside the nucleus in the membraneless nucleolus Boisvert et al.
The nucleolus can expand or retract to address cellular needs for ribosomal biogenesis, and fibrillarin levels have been correlated with nucleolar expansion Weber and Brangwynne , which stimulates the rate of ribosome assembly Tollervey et al.
Interestingly, proteins that become unstable in the nucleus can accumulate inside nucleoli Frottin et al. Ribosomal subunits that are translated in the cytoplasm require nuclear import to assemble with processed rRNAs. Subsequently, newly assembled rRNA-containing ribosomal subunits are exported out of the nucleus and combine to form large 80S ribosomes for mRNA translation. Notably, when exported in the cytoplasm, supernumerous ribosomal subunits An and Harper ; Sung et al.
Several long-lived nematodes display smaller nucleoli, in part via lower FIB-1, rRNA, and ribosomal protein levels, and specifically silencing fib-1 extends lifespan in C. High levels of FBL expression are found in several cancers Koh et al. TRIM2 mutations in humans are linked to axonal neurodegeneration Ylikallio et al. Different environmental stresses, including nucleotide depletion, heat shock, hypoxia, or UV, generate a nucleolar stress response Rubbi and Milner ; Yang et al.
This response elicits a signaling cascade mediated in part by p53 Nicolas et al. Another environmental stress, starvation, results in chaperones heat shock proteins repartitioning into the nucleus Chughtai et al. Aggregated nucleoplasmic proteins can accumulate in the nucleolus Latonen , in particular when proteasome function is compromised Latonen et al.
In yeast, acute heat stress leads to the reversible formation of nucleolar protein aggregates Gallardo et al. The nucleolus is also a temporary store for epigenetic regulators during heat shock, which are subsequently functionally restored after recovery from heat stress Azkanaz et al.
Aggregates in the nucleus have also been found in depots called intranuclear quality control compartment INQ Miller et al. Interestingly, there are mechanistic links between nucleolar stress and autophagy Pfister , and nucleolar proteins can be degraded via nucleophagy Mostofa et al. Heat shock proteins serve as chaperones and are found in both the nucleus and the cytoplasm Echtenkamp and Freeman ; Vabulas et al.
They modulate protein aggregation by converting unstable proteins into their native fold or into manageable proteasome targets den Brave et al. Cryo-electron microscopy imaging of the nuclear pore in the green alga Chlamydomonas reinhardtii demonstrated tethering and enrichment of 26S proteasomes at the nuclear basket side Albert et al. Studies in the yeast S. Recently, a study demonstrated that the accumulation of selective autophagy receptor SQSTM1 in nuclear condensates, brought about by reducing nuclear protein export, improves proteasomal function and degradation of c-myc, a key regulator of ribosome biogenesis and nucleolar dynamics Fu et al.
Thus, nuclear localization of autophagy-related factors can modulate different proteostatic mechanisms and impact proteostasis globally. Altogether, these studies highlight the ability of cells to sequester nuclear proteins into condensates or around the nuclear pore in order to determine their fate.
The cytoplasm encompasses several membrane-bound organelles that interact with each other and mediate and integrate key cellular functions Cohen et al. As organisms age, organelles accumulate damage and need to be degraded.
Bulk degradation of these organelles is mediated by the recycling process of autophagy and lysosomal degradation Galluzzi et al. Selective sequestration of organelles is mediated by selective autophagy receptors that recognize damaged organelles and facilitate their degradation Zaffagnini and Martens For instance, efficient degradation of mitochondria via mitophagy is required in the lifespan extension of long-lived nematodes Palikaras et al.
Concomitantly, cytoplasmic 26S proteasomes degrade a vast array of damaged and ubiquitinated proteins. When proteostatic and protein degradation machineries are overwhelmed, aggregating proteins can accumulate in specific sites in the cytoplasm called the insoluble protein depot IPOD and the juxtanuclear quality control JUNQ compartments Samant et al.
In specific proteostatic challenges, cells can activate organelle-specific unfolded protein responses UPR ER or UPR MT Shpilka and Haynes ; Walter and Ron , which results in enhancement in protein folding in order to ensure solubility and function. The ER and mitochondria also possess lumenal proteases that directly degrade proteins synthesized or imported Quiros et al.
In yeast, mitochondria can degrade resident proteins Hughes et al. The ER can also send proteins to the proteasome via ER-associated degradation ERAD where polypeptides are recognized and threaded back into the cytosol via a retro-translocon Brodsky ; Qi et al. Lipid droplets can serve as an intermediary organelle for ERAD where cargo bound for degradation transit on the lipid droplet surface before being degraded by the proteasome Olzmann and Carvalho The endosomal sorting complexes required for transport ESCRT is a multisubunit complex tasked with sorting ubiquitinated proteins and multi-vesicular bodies toward lysosomal degradation Schmidt and Teis Compromised ESCRT leads to the autophagic dysfunction and accumulation of aggregating proteins relevant to neurodegeneration Oshima et al.
Notably, proteins associated with the lysosomal membrane can be degraded by lysosomes via the ESCRT machinery Zhu et al. Overall, the cytoplasm possesses several options to stabilize or degrade proteins, but aging systematically decreases the ability of this compartment to properly manage proteostasis, resulting in molecular crowding and aggregated protein deposition. Cells employ an arsenal of mechanisms to maintain protein homeostasis in order to ensure cell survival and to adapt to changing environments.
In addition to compartment-specific proteostatic processes, the integration of different mechanisms such as nucleolar dynamics and autophagy Pfister generates a global response against proteotoxic stress associated with aging. Signaling between different organelles, such as mitochondria and nucleus Fang et al.
Signaling pathways that can coordinate a proteostatic response, such as nutrient signaling mediated by mTOR complexes Laplante and Sabatini and the integrated stress response via the eIF2 complex Costa-Mattioli and Walter , are important mechanisms to balance protein synthesis and degradation.
These processes modify ribosome biogenesis and function, protein specification, and localization, and ultimately affect the stability of the proteome. An important mechanism of proteostasis that potentially fails during aging is the proper partitioning of proteins across the nuclear pore Fig.
Mislocalization of proteins fosters aggregation, but concomitant aberrant DNA release into the cytoplasm can also lead to inflammation and neurodegeneration Paul et al. Therefore, pharmacologically modulating the nucleocytoplasmic partitioning of proteins is emerging as an attractive strategy to impact the stability of the whole proteome and delay aging. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Biophys Rev. Published online Nov Anita V. Kumar and Louis R. Louis R. Author information Article notes Copyright and License information Disclaimer.
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This article has been cited by other articles in PMC. Abstract Somatic maintenance and cell survival rely on proper protein homeostasis to ensure reliable functions across the cell and to prevent proteome collapse. Keywords: C. Introduction One of the key hallmarks of aging is the loss of protein homeostasis Lopez-Otin et al. Open in a separate window. Nucleocytoplasmic protein trafficking Proteome partitioning between the cytoplasm and the nucleus is mediated by passive and facilitated transport of proteins across the nuclear pore Knockenhauer and Schwartz ; Timney et al.
Coordination of nucleocytoplasmic protein partitioning and proteostatic mechanisms. Nuclear proteostasis: nexus of ribosomal subunit and protein quality control The nuclear proteome is diverse and requires proper protein surveillance in order to maintain nuclear structure and dynamic processes that characterize this essential organelle Enam et al.
Cytoplasmic proteostasis: organelle-specific and bulk protein quality control The cytoplasm encompasses several membrane-bound organelles that interact with each other and mediate and integrate key cellular functions Cohen et al.
Conclusion Cells employ an arsenal of mechanisms to maintain protein homeostasis in order to ensure cell survival and to adapt to changing environments. Nucleocytoplasmic proteostatic inter-relationship during aging. Funding L. Declarations Conflict of interest The authors declare no competing interests. Footnotes Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Proteasomes tether to two distinct sites at the nuclear pore complex.
Ribosome abundance control via the ubiquitin-proteasome system and autophagy. J Mol Biol. The nuclear pore complex: understanding its function through structural insight. Nat Rev Mol Cell Biol. Quality control compartments coming of age. Collapse of proteostasis represents an early molecular event in Caenorhabditis elegans aging. The multifunctional nucleolus. Mol Cell. Cleaning up: ER-associated degradation to the rescue.
The RanGTP pathway: from nucleo-cytoplasmic transport to spindle assembly and beyond. Front Cell Dev Biol. Safety and efficacy of selinexor in relapsed or refractory multiple myeloma and Waldenstrom macroglobulinemia. Nuclear import by karyopherin-betas: recognition and inhibition.
Biochim Biophys Acta. Starvation promotes nuclear accumulation of the hsp70 Ssa4p in yeast cells. J Biol Chem. Widespread aggregation and neurodegenerative diseases are associated with supersaturated proteins. Cell Rep. Reduced IGF-1 signaling delays age-associated proteotoxicity in mice. Interacting organelles. Curr Opin Cell Biol. Science Structure, dynamics and function of nuclear pore complexes. Trends Cell Biol.
Widespread protein aggregation as an inherent part of aging in C. PLoS Biol. Chaperone-mediated protein disaggregation triggers proteolytic clearance of intra-nuclear protein inclusions. Emerging topics in C. Mech Ageing Dev.
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