•Curcumin ameliorates aging-related cellular and organ dysfunctions.•Curcumin nanoformulations overcome therapeutic obstacles for free curcumin.•Nano-curcumin is suitable to treat diverse ...aging-related diseases or disorders.•Nano-curcumin has been tested for neurodegeneration, cancer, diabetes, infection, arthritis.•Potential clinical applications of nano-curcumin are emerging.
Aging increases the susceptibility to a diverse set of diseases and disorders, including neurodegeneration, cancer, diabetes, and arthritis. Natural compounds are currently being explored as alternative or complementary agents to treat or prevent aging-related malfunctions. Curcumin, a phytochemical isolated from the spice turmeric, has garnered great interest in recent years. With anti-oxidant, anti-inflammatory, anti-microbial, and other physiological activities, curcumin has great potential for health applications. However, the benefits of curcumin are restricted by its low bioavailability and stability in biological systems. Curcumin nanoformulations, or nano-curcumin, may overcome these limitations. This review discusses different forms of nano-curcumin that have been evaluated in vitro and in vivo to treat or prevent aging-associated health impairments. We describe current barriers for the routine use of curcumin nanoformulations in the clinic. Our review highlights outstanding questions and future work that is needed to ensure nano-curcumin is efficient and safe to lessen the burden of aging-related health problems.
Cytoplasmic RNA granules represent subcellular compartments that are enriched in protein-bound RNA species. RNA granules are produced by evolutionary divergent eukaryotes, including yeast, mammals, ...and plants. The functions of cytoplasmic RNA granules differ widely. They are dictated by the cell type and physiological state, which in turn is determined by intrinsic cell properties and environmental factors. RNA granules provide diverse cellular functions. However, all of the granules contribute to aspects of RNA metabolism. This is exemplified by transcription, RNA storage, silencing, and degradation, as well as mRNP remodeling and regulated translation. Several forms of cytoplasmic mRNA granules are linked to normal physiological processes. For instance, they may coordinate protein synthesis and thereby serve as posttranscriptional "operons". RNA granules also participate in cytoplasmic mRNA trafficking, a process particularly well understood for neurons. Many forms of RNA granules support the preservation of somatic cell performance under normal and stress conditions. On the other hand, severe insults or disease can cause the formation and persistence of RNA granules that contribute to cellular dysfunction, especially in the nervous system. Neurodegeneration and many other diseases linked to RNA granules are associated with aging. Nevertheless, information related to the impact of aging on the various types of RNA granules is presently very limited. This review concentrates on cytoplasmic RNA granules and their role in somatic cell maintenance. We summarize the current knowledge on different types of RNA granules in the cytoplasm, their assembly and function under normal, stress, or disease conditions. Specifically, we discuss processing bodies, neuronal granules, stress granules, and other less characterized cytoplasmic RNA granules. Our focus is primarily on mammalian and yeast models, because they have been critical to unravel the physiological role of various RNA granules. RNA granules in plants and pathogens are briefly described. We conclude our viewpoint by summarizing the emerging concepts for RNA granule biology and the open questions that need to be addressed in future studies.
The AAA
ATPase valosin containing protein (VCP) is essential for cell and organ homeostasis, especially in cells of the nervous system. As part of a large network, VCP collaborates with many ...cofactors to ensure proteostasis under normal, stress, and disease conditions. A large number of mutations have revealed the importance of VCP for human health. In particular, VCP facilitates the dismantling of protein aggregates and the removal of dysfunctional organelles. These are critical events to prevent malfunction of the brain and other parts of the nervous system. In line with this idea, VCP mutants are linked to the onset and progression of neurodegeneration and other diseases. The intricate molecular mechanisms that connect VCP mutations to distinct brain pathologies continue to be uncovered. Emerging evidence supports the model that VCP controls cellular functions on multiple levels and in a cell type specific fashion. Accordingly, VCP mutants derail cellular homeostasis through several mechanisms that can instigate disease. Our review focuses on the association between VCP malfunction and neurodegeneration. We discuss the latest insights in the field, emphasize open questions, and speculate on the potential of VCP as a drug target for some of the most devastating forms of neurodegeneration.
Nuclear protein trafficking requires the soluble transport factor RanBP1. The subcellular distribution of RanBP1 is dynamic, as the protein shuttles between the nucleus and cytoplasm. To date, the ...signaling pathways regulating RanBP1 subcellular localization are poorly understood. During interphase, RanBP1 resides mostly in the cytoplasm. We show here that oxidative stress concentrates RanBP1 in the nucleus, and our study defines the underlying mechanisms. Specifically, RanBP1’s cysteine residues are not essential for its oxidant-induced relocation. Furthermore, our pharmacological approaches uncover that signaling mediated by epidermal growth factor receptor (EGFR) and protein kinase A (PKA) control RanBP1 localization during stress. In particular, pharmacological inhibitors of EGFR or PKA diminish the oxidant-dependent relocation of RanBP1. Mutant analysis identified serine 60 and tyrosine 103 as regulators of RanBP1 nuclear accumulation during oxidant exposure. Taken together, our results define RanBP1 as a target of oxidative stress and a downstream effector of EGFR and PKA signaling routes. This positions RanBP1 at the intersection of important cellular signaling circuits.
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•Oxidant exposure concentrates RanBP1 in the nucleus.•RanBP1 cysteine residues are not required for oxidant-induced nuclear concentration.•Residues Ser60 and Tyr103 control RanBP1 nuclear accumulation during stress.•EGFR and PKA signaling pathways modulate RanBP1 concentration in nuclei.
Nucleoli and cytoplasmic stress granules (SGs) are subcellular compartments that modulate the response to endogenous and environmental signals to control cell survival. In our opinion, nucleoli and ...SGs are functionally linked; they are distant relatives that combine forces when cellular homeostasis is threatened. Several lines of evidence support this idea; nucleoli and SGs share molecular building blocks, are regulated by common signaling pathways and communicate when vital cellular functions become compromised. Together, nucleoli and SGs orchestrate physiological responses that are directly relevant to stress and human health. As both compartments have established roles in neurodegenerative diseases, cancer and virus infections, we propose that these conditions will benefit from therapeutic interventions that target simultaneously nucleoli and SGs.
Nucleoli and cytoplasmic stress granules (SGs) are subcellular compartments that modulate the response to endogenous and environmental signals to control cell survival. In our opinion, nucleoli and SGs are functionally linked; they are distant relatives that combine forces when cellular homeostasis is threatened. Given that nucleoli and SGs orchestrate physiological responses that are directly relevant to human health, we propose that several conditions including neurodegeneration, cancer and virus infections will benefit from therapeutic interventions that target simultaneously both compartments.
Stress granule (SG) assembly is a conserved cellular strategy to minimize stress-related damage and promote cell survival. Beyond their fundamental role in the stress response, SGs have emerged as ...key players for human health. As such, SG assembly is associated with cancer, neurodegenerative disorders, ischemia, and virus infections. SGs and granule-related signaling circuits are therefore promising targets to improve therapeutic intervention for several diseases. This is clinically relevant, because pharmacological drugs can affect treatment outcome by modulating SG formation.
As membraneless and highly dynamic compartments, SGs regulate translation, ribostasis and proteostasis. Moreover, they serve as signaling hubs that determine cell viability and stress recovery. Various compounds can modulate SG formation and dynamics. Rewiring cell signaling through SG manipulation thus represents a new strategy to control cell fate under various physiological and pathological conditions.
•Stress granule assembly minimizes stress-related damage and promotes cell survival.•Stress granules constitute signaling hubs that can rewire signal transduction.•Stress granules play an essential role for human health.•Pharmacological compounds can modulate stress granule formation.•Stress granules represent promising therapeutic targets for many pathologies.
The Cytoskeleton as Regulator of Cell Signaling Pathways Moujaber, Ossama; Stochaj, Ursula
Trends in biochemical sciences (Amsterdam. Regular ed.),
February 2020, 2020-02-00, 20200201, Letnik:
45, Številka:
2
Journal Article
Recenzirano
During interphase, filamentous actin, microtubules, and intermediate filaments regulate cell shape, motility, transport, and interactions with the environment. These activities rely on signaling ...events that control cytoskeleton properties. Recent studies uncovered mechanisms that go far beyond this one-directional flow of information. Thus, the three branches of the cytoskeleton impinge on signaling pathways to determine their activities. We propose that this regulatory role of the cytoskeleton provides sophisticated mechanisms to control the spatiotemporal output and the intensity of signaling events. Specific examples emphasize these emerging contributions of the cytoskeleton to cell physiology. In our opinion, further exploration of these pathways will uncover new concepts of cellular communication that originate from the cytoskeleton.
The actin cytoskeleton, microtubules, and intermediate filaments control cell signaling. Several filament systems can cooperate to regulate the same signaling pathway.The cytoskeleton regulates the location, duration, and intensity of signaling through a diverse set of mechanisms. These mechanisms range from force generation to sequestration of signaling regulators.The PI3 kinase‒Akt and Rho‒Rock pathways are major targets for cytoskeleton-dependent control. At the same time, these signaling routes also regulate cytoskeletal properties.Different isoforms of filament building blocks are produced, often in a cell type-dependent fashion. The combination of isoforms and numerous post-translational modifications generate actin, microtubule, or intermediate filaments that are highly heterogeneous. This heterogeneity could fine-tune the signaling control elicited by the cytoskeleton.
Stress granule (SG) assembly represents a conserved eukaryotic defense strategy against various insults. Although essential for the ability to cope with deleterious conditions, the signaling pathways ...controlling SG formation are not fully understood. The energy sensor AMP-activated protein kinase (AMPK) is critical for the cellular stress response. Human cells produce two AMPK catalytic α-subunits with not only partially overlapping, but also unique functions. Here, we provide direct support for structural and functional links between AMPK-α isoforms and SGs. As such, several stressors promote SG association of AMPK-α2, but not AMPK-α1. Multiple lines of evidence link AMPK activity to SG biogenesis. First, pharmacological kinase inhibition interfered with SG formation. Second, AMPK-α knockdown combined with in-depth quantitative SG analysis revealed isoform-specific changes of SG characteristics. Third, overexpression of mutant α-subunits further substantiated that AMPK regulates SG parameters. Finally, we identified the SG-nucleating protein G3BP1 as an AMPK-α2 binding partner. This interaction is stimulated by stress and notably occurs in SGs. Collectively, our data define the master metabolic regulator AMPK as a novel SG constituent that also controls their biogenesis.
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•AMPK-α2 is a bona fide component of cytoplasmic stress granules.•AMPK-α controls the biogenesis of cytoplasmic stress granules.•AMPK-α2 binds directly to the granule nucleating protein G3BP1 in stress granules.•Stress stimulates the interaction between AMPK-α2 and G3BP1.
Importin-α1 belongs to a subfamily of nuclear transport adaptors and participates in diverse cellular functions. Best understood for its role in protein transport, importin-α1 also contributes to ...other biological processes. For instance, arsenite treatment causes importin-α1 to associate with cytoplasmic stress granules (SGs) in mammalian cells. These stress-induced compartments contain translationally arrested mRNAs, small ribosomal subunits and numerous proteins involved in mRNA transport and metabolism. At present, it is not known whether members of all three importin-α subfamilies locate to SGs in response to stress.
Here, we demonstrate that the oxidant diethyl maleate (DEM), arsenite and heat shock, promote the formation of cytoplasmic SGs that contain nuclear transport factors. Specifically, importin-α1, α4 and α5, which belong to distinct subfamilies, and importin-β1 were targeted by all of these stressors to cytoplasmic SGs, but not to P-bodies. Importin-α family members have been implicated in transcriptional regulation, which prompted us to analyze their ability to interact with poly(A)-RNA in growing cells. Our studies show that importin-α1, but not α4, α5, importin-β1 or CAS, associated with poly(A)-RNA under nonstress conditions. Notably, this interaction was significantly reduced when cells were treated with DEM. Additional studies suggest that importin-α1 is likely connected to poly(A)-RNA through an indirect interaction, as the adaptor did not bind homopolymer RNA specifically in vitro.
Our studies establish that members of three importin-α subfamilies are bona fide SG components under different stress conditions. Furthermore, importin-α1 is unique in its ability to interact with poly(A)-RNA in a stress-dependent fashion, and in vitro experiments indicate that this association is indirect. Collectively, our data emphasize that nuclear transport factors participate in a growing number of cellular activities that are modulated by stress.
Profilin is a small protein that controls actin polymerization in yeast and higher eukaryotes. In addition, profilin has emerged as a multifunctional protein that contributes to other processes in ...multicellular organisms. This study focuses on profilin (Pfy1) in the budding yeast
The primary sequences of yeast Pfy1 and its metazoan orthologs diverge vastly. However, structural elements of profilin are conserved among different species. To date, the full spectrum of Pfy1 functions has yet to be defined. The current work explores the possible involvement of yeast profilin in nuclear protein import. To this end, a panel of well-characterized yeast profilin mutants was evaluated. The experiments demonstrate that yeast profilin (
) regulates nuclear protein import, (
) determines the subcellular localization of essential nuclear transport factors, and (
) controls the relative abundance of actin and tubulin. Together, these results define yeast profilin as a moonlighting protein that engages in multiple essential cellular activities.
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