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Cells, Volume 5, Issue 1 (March 2016)

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Open AccessArticle
Src1 is a Protein of the Inner Nuclear Membrane Interacting with the Dictyostelium Lamin NE81
Received: 29 January 2016 / Revised: 9 March 2016 / Accepted: 11 March 2016 / Published: 18 March 2016
Cited by 8 | Viewed by 2879 | PDF Full-text (5038 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The nuclear envelope (NE) consists of the outer and inner nuclear membrane (INM), whereby the latter is bound to the nuclear lamina. Src1 is a Dictyostelium homologue of the helix-extension-helix family of proteins, which also includes the human lamin-binding protein MAN1. Both endogenous [...] Read more.
The nuclear envelope (NE) consists of the outer and inner nuclear membrane (INM), whereby the latter is bound to the nuclear lamina. Src1 is a Dictyostelium homologue of the helix-extension-helix family of proteins, which also includes the human lamin-binding protein MAN1. Both endogenous Src1 and GFP-Src1 are localized to the NE during the entire cell cycle. Immuno-electron microscopy and light microscopy after differential detergent treatment indicated that Src1 resides in the INM. FRAP experiments with GFP-Src1 cells suggested that at least a fraction of the protein could be stably engaged in forming the nuclear lamina together with the Dictyostelium lamin NE81. Both a BioID proximity assay and mis-localization of soluble, truncated mRFP-Src1 at cytosolic clusters consisting of an intentionally mis-localized mutant of GFP-NE81 confirmed an interaction of Src1 and NE81. Expression GFP-Src11–646, a fragment C-terminally truncated after the first transmembrane domain, disrupted interaction of nuclear membranes with the nuclear lamina, as cells formed protrusions of the NE that were dependent on cytoskeletal pulling forces. Protrusions were dependent on intact microtubules but not actin filaments. Our results indicate that Src1 is required for integrity of the NE and highlight Dictyostelium as a promising model for the evolution of nuclear architecture. Full article
(This article belongs to the collection Lamins and Laminopathies)
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Open AccessFeature PaperReview
The Regulation of NF-κB Subunits by Phosphorylation
Received: 26 February 2016 / Revised: 9 March 2016 / Accepted: 14 March 2016 / Published: 18 March 2016
Cited by 107 | Viewed by 3914 | PDF Full-text (626 KB) | HTML Full-text | XML Full-text
Abstract
The NF-κB transcription factor is the master regulator of the inflammatory response and is essential for the homeostasis of the immune system. NF-κB regulates the transcription of genes that control inflammation, immune cell development, cell cycle, proliferation, and cell death. The fundamental role [...] Read more.
The NF-κB transcription factor is the master regulator of the inflammatory response and is essential for the homeostasis of the immune system. NF-κB regulates the transcription of genes that control inflammation, immune cell development, cell cycle, proliferation, and cell death. The fundamental role that NF-κB plays in key physiological processes makes it an important factor in determining health and disease. The importance of NF-κB in tissue homeostasis and immunity has frustrated therapeutic approaches aimed at inhibiting NF-κB activation. However, significant research efforts have revealed the crucial contribution of NF-κB phosphorylation to controlling NF-κB directed transactivation. Importantly, NF-κB phosphorylation controls transcription in a gene-specific manner, offering new opportunities to selectively target NF-κB for therapeutic benefit. This review will focus on the phosphorylation of the NF-κB subunits and the impact on NF-κB function. Full article
(This article belongs to the Special Issue Cellular and Molecular Biology of NF-κB)
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Open AccessFeature PaperReview
Rab GTPases and the Autophagy Pathway: Bacterial Targets for a Suitable Biogenesis and Trafficking of Their Own Vacuoles
Received: 26 January 2016 / Revised: 2 March 2016 / Accepted: 3 March 2016 / Published: 8 March 2016
Cited by 11 | Viewed by 4168 | PDF Full-text (769 KB) | HTML Full-text | XML Full-text
Abstract
Autophagy is an intracellular process that comprises degradation of damaged organelles, protein aggregates and intracellular pathogens, having an important role in controlling the fate of invading microorganisms. Intracellular pathogens are internalized by professional and non-professional phagocytes, localizing in compartments called phagosomes. To degrade [...] Read more.
Autophagy is an intracellular process that comprises degradation of damaged organelles, protein aggregates and intracellular pathogens, having an important role in controlling the fate of invading microorganisms. Intracellular pathogens are internalized by professional and non-professional phagocytes, localizing in compartments called phagosomes. To degrade the internalized microorganism, the microbial phagosome matures by fusion events with early and late endosomal compartments and lysosomes, a process that is regulated by Rab GTPases. Interestingly, in order to survive and replicate in the phagosome, some pathogens employ different strategies to manipulate vesicular traffic, inhibiting phagolysosomal biogenesis (e.g., Staphylococcus aureus and Mycobacterium tuberculosis) or surviving in acidic compartments and forming replicative vacuoles (e.g., Coxiella burnetti and Legionella pneumophila). The bacteria described in this review often use secretion systems to control the host’s response and thus disseminate. To date, eight types of secretion systems (Type I to Type VIII) are known. Some of these systems are used by bacteria to translocate pathogenic proteins into the host cell and regulate replicative vacuole formation, apoptosis, cytokine responses, and autophagy. Herein, we have focused on how bacteria manipulate small Rab GTPases to control many of these processes. The growing knowledge in this field may facilitate the development of new treatments or contribute to the prevention of these types of bacterial infections. Full article
(This article belongs to the Special Issue Regulation and Function of Small GTPases)
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Open AccessFeature PaperReview
Hypoxia Induced NF-κB
Received: 28 January 2016 / Revised: 1 March 2016 / Accepted: 3 March 2016 / Published: 8 March 2016
Cited by 20 | Viewed by 2603 | PDF Full-text (562 KB) | HTML Full-text | XML Full-text
Abstract
As Nuclear Factor-κB (NF-κB) is a major transcription factor responding to cellular stress, it is perhaps not surprising that is activated by hypoxia, or decreased oxygen availability. However, how NF-κB becomes activated in hypoxia is still not completely understood. Several mechanisms have been [...] Read more.
As Nuclear Factor-κB (NF-κB) is a major transcription factor responding to cellular stress, it is perhaps not surprising that is activated by hypoxia, or decreased oxygen availability. However, how NF-κB becomes activated in hypoxia is still not completely understood. Several mechanisms have been proposed and this review will focus on the main findings highlighting the molecules that have been identified in the process of hypoxia induced NF-κB. In addition, we will discuss the role of NF-κB in the control of the cellular response to hypoxia. Full article
(This article belongs to the Special Issue Cellular and Molecular Biology of NF-κB)
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Open AccessReview
The Trypanosome Flagellar Pocket Collar and Its Ring Forming Protein—TbBILBO1
Received: 22 December 2015 / Revised: 19 February 2016 / Accepted: 23 February 2016 / Published: 2 March 2016
Cited by 4 | Viewed by 2474 | PDF Full-text (2655 KB) | HTML Full-text | XML Full-text
Abstract
Sub-species of Trypanosoma brucei are the causal agents of human African sleeping sickness and Nagana in domesticated livestock. These pathogens have developed an organelle-like compartment called the flagellar pocket (FP). The FP carries out endo- and exocytosis and is the only structure this [...] Read more.
Sub-species of Trypanosoma brucei are the causal agents of human African sleeping sickness and Nagana in domesticated livestock. These pathogens have developed an organelle-like compartment called the flagellar pocket (FP). The FP carries out endo- and exocytosis and is the only structure this parasite has evolved to do so. The FP is essential for parasite viability, making it an interesting structure to evaluate as a drug target, especially since it has an indispensible cytoskeleton component called the flagellar pocket collar (FPC). The FPC is located at the neck of the FP where the flagellum exits the cell. The FPC has a complex architecture and division cycle, but little is known concerning its organization. Recent work has focused on understanding how the FP and the FPC are formed and as a result of these studies an important calcium-binding, polymer-forming protein named TbBILBO1 was identified. Cellular biology analysis of TbBILBO1 has demonstrated its uniqueness as a FPC component and until recently, it was unknown what structural role it played in forming the FPC. This review summarizes the recent data on the polymer forming properties of TbBILBO1 and how these are correlated to the FP cytoskeleton. Full article
(This article belongs to the Special Issue Cilia and Flagella: Biogenesis and Function)
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Open AccessArticle
Matefin/SUN-1 Phosphorylation on Serine 43 Is Mediated by CDK-1 and Required for Its Localization to Centrosomes and Normal Mitosis in C. elegans Embryos
Received: 31 December 2015 / Revised: 8 February 2016 / Accepted: 8 February 2016 / Published: 24 February 2016
Cited by 3 | Viewed by 2291 | PDF Full-text (4295 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Matefin/SUN-1 is an evolutionary conserved C. elegans inner nuclear membrane SUN-domain protein. By creating a bridge with the KASH-domain protein ZYG-12, it connects the nucleus to cytoplasmic filaments and organelles. Matefin/SUN-1 is expressed in the germline where it undergoes specific phosphorylation at its [...] Read more.
Matefin/SUN-1 is an evolutionary conserved C. elegans inner nuclear membrane SUN-domain protein. By creating a bridge with the KASH-domain protein ZYG-12, it connects the nucleus to cytoplasmic filaments and organelles. Matefin/SUN-1 is expressed in the germline where it undergoes specific phosphorylation at its N-terminal domain, which is required for germline development and homologous chromosome pairing. The maternally deposited matefin/SUN-1 is then essential for embryonic development. Here, we show that in embryos, serine 43 of matefin/SUN-1 (S43) is phosphorylated in a CDK-1 dependent manner and is localized throughout the cell cycle mostly to centrosomes. By generating animals expressing phosphodead S43A and phosphomimetic S43E mutations, we show that phosphorylation of S43 is required to maintain centrosome integrity and function, as well as for the localization of ZYG-12 and lamin. Expression of S43E in early embryos also leads to an increase in chromatin structural changes, decreased progeny and to almost complete embryonic lethality. Down regulation of emerin further increases the occurrence of chromatin organization abnormalities, indicating possible collaborative roles for these proteins that is regulated by S43 phosphorylation. Taken together, these results support a role for phosphorylation of serine 43 in matefin/SUN-1 in mitosis. Full article
(This article belongs to the collection Lamins and Laminopathies)
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Open AccessReview
Functions of Rab Proteins at Presynaptic Sites
Received: 12 January 2016 / Accepted: 3 February 2016 / Published: 6 February 2016
Cited by 14 | Viewed by 3281 | PDF Full-text (641 KB) | HTML Full-text | XML Full-text
Abstract
Presynaptic neurotransmitter release is dominated by the synaptic vesicle (SV) cycle and entails the biogenesis, fusion, recycling, reformation or turnover of synaptic vesicles—a process involving bulk movement of membrane and proteins. As key mediators of membrane trafficking, small GTPases from the Rab family [...] Read more.
Presynaptic neurotransmitter release is dominated by the synaptic vesicle (SV) cycle and entails the biogenesis, fusion, recycling, reformation or turnover of synaptic vesicles—a process involving bulk movement of membrane and proteins. As key mediators of membrane trafficking, small GTPases from the Rab family of proteins play critical roles in this process by acting as molecular switches that dynamically interact with and regulate the functions of different sets of macromolecular complexes involved in each stage of the cycle. Importantly, mutations affecting Rabs, and their regulators or effectors have now been identified that are implicated in severe neurological and neurodevelopmental disorders. Here, we summarize the roles and functions of presynaptic Rabs and discuss their involvement in the regulation of presynaptic function. Full article
(This article belongs to the Special Issue Regulation and Function of Small GTPases)
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Open AccessReview
Cellular Mechanisms of Ciliary Length Control
Received: 22 September 2015 / Revised: 21 January 2016 / Accepted: 25 January 2016 / Published: 29 January 2016
Cited by 23 | Viewed by 3731 | PDF Full-text (629 KB) | HTML Full-text | XML Full-text
Abstract
Cilia and flagella are evolutionarily conserved, membrane-bound, microtubule-based organelles on the surface of most eukaryotic cells. They play important roles in coordinating a variety of signaling pathways during growth, development, cell mobility, and tissue homeostasis. Defects in ciliary structure or function are associated [...] Read more.
Cilia and flagella are evolutionarily conserved, membrane-bound, microtubule-based organelles on the surface of most eukaryotic cells. They play important roles in coordinating a variety of signaling pathways during growth, development, cell mobility, and tissue homeostasis. Defects in ciliary structure or function are associated with multiple human disorders called ciliopathies. These diseases affect diverse tissues, including, but not limited to the eyes, kidneys, brain, and lungs. Many processes must be coordinated simultaneously in order to initiate ciliogenesis. These include cell cycle, vesicular trafficking, and axonemal extension. Centrioles play a central role in both cell cycle progression and ciliogenesis, making the transition between basal bodies and mitotic spindle organizers integral to both processes. The maturation of centrioles involves a functional shift from cell division toward cilium nucleation which takes place concurrently with its migration and fusion to the plasma membrane. Several proteinaceous structures of the distal appendages in mother centrioles are required for this docking process. Ciliary assembly and maintenance requires a precise balance between two indispensable processes; so called assembly and disassembly. The interplay between them determines the length of the resulting cilia. These processes require a highly conserved transport system to provide the necessary substances at the tips of the cilia and to recycle ciliary turnover products to the base using a based microtubule intraflagellar transport (IFT) system. In this review; we discuss the stages of ciliogenesis as well as mechanisms controlling the lengths of assembled cilia. Full article
(This article belongs to the Special Issue Cilia and Flagella: Biogenesis and Function)
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Open AccessEditorial
Acknowledgement to Reviewers of Cells in 2015
Received: 27 January 2016 / Accepted: 27 January 2016 / Published: 27 January 2016
Viewed by 1323 | PDF Full-text (136 KB) | HTML Full-text | XML Full-text
Abstract
The editors of Cells would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2015. [...] Full article
Open AccessReview
Feedback Regulation of Kinase Signaling Pathways by AREs and GREs
Received: 11 December 2015 / Revised: 20 January 2016 / Accepted: 20 January 2016 / Published: 25 January 2016
Cited by 7 | Viewed by 2348 | PDF Full-text (1197 KB) | HTML Full-text | XML Full-text
Abstract
In response to environmental signals, kinases phosphorylate numerous proteins, including RNA-binding proteins such as the AU-rich element (ARE) binding proteins, and the GU-rich element (GRE) binding proteins. Posttranslational modifications of these proteins lead to a significant changes in the abundance of target mRNAs, [...] Read more.
In response to environmental signals, kinases phosphorylate numerous proteins, including RNA-binding proteins such as the AU-rich element (ARE) binding proteins, and the GU-rich element (GRE) binding proteins. Posttranslational modifications of these proteins lead to a significant changes in the abundance of target mRNAs, and affect gene expression during cellular activation, proliferation, and stress responses. In this review, we summarize the effect of phosphorylation on the function of ARE-binding proteins ZFP36 and ELAVL1 and the GRE-binding protein CELF1. The networks of target mRNAs that these proteins bind and regulate include transcripts encoding kinases and kinase signaling pathways (KSP) components. Thus, kinase signaling pathways are involved in feedback regulation, whereby kinases regulate RNA-binding proteins that subsequently regulate mRNA stability of ARE- or GRE-containing transcripts that encode components of KSP. Full article
(This article belongs to the Special Issue Signal Transduction 2016)
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Open AccessReview
The Role of G-Protein-Coupled Receptor Proteolysis Site Cleavage of Polycystin-1 in Renal Physiology and Polycystic Kidney Disease
Received: 3 December 2015 / Revised: 18 January 2016 / Accepted: 19 January 2016 / Published: 21 January 2016
Cited by 7 | Viewed by 2975 | PDF Full-text (875 KB) | HTML Full-text | XML Full-text
Abstract
Polycystin-1 (PC1) plays an essential role in renal tubular morphogenesis, and PC1 dysfunction causes human autosomal dominant polycystic kidney disease. A fundamental characteristic of PC1 is post-translational modification via cleavage at the juxtamembrane GPCR proteolysis site (GPS) motif that is part of the [...] Read more.
Polycystin-1 (PC1) plays an essential role in renal tubular morphogenesis, and PC1 dysfunction causes human autosomal dominant polycystic kidney disease. A fundamental characteristic of PC1 is post-translational modification via cleavage at the juxtamembrane GPCR proteolysis site (GPS) motif that is part of the larger GAIN domain. Given the considerable biochemical complexity of PC1 molecules generated in vivo by this process, GPS cleavage has several profound implications on the intracellular trafficking and localization in association with their particular function. The critical nature of GPS cleavage is further emphasized by the increasing numbers of PKD1 mutations that significantly affect this cleavage process. The GAIN domain with the GPS motif therefore represents the key structural element with fundamental importance for PC1 and might be polycystic kidney disease’s (PKD) Achilles’ heel in a large spectrum of PKD1 missense mutations. We highlight the central roles of PC1 cleavage for the regulation of its biogenesis, intracellular trafficking and function, as well as its significance in polycystic kidney disease. Full article
(This article belongs to the Special Issue The Kidney: Development, Disease and Regeneration)
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Open AccessReview
Re-Use of Established Drugs for Anti-Metastatic Indications
Received: 21 November 2015 / Revised: 4 January 2016 / Accepted: 8 January 2016 / Published: 12 January 2016
Cited by 4 | Viewed by 1844 | PDF Full-text (523 KB) | HTML Full-text | XML Full-text
Abstract
Most patients that die from cancer do not die due to the primary tumor but due to the development of metastases. However, there is currently still no drug on the market that specifically addresses and inhibits metastasis formation. This lack was, in the [...] Read more.
Most patients that die from cancer do not die due to the primary tumor but due to the development of metastases. However, there is currently still no drug on the market that specifically addresses and inhibits metastasis formation. This lack was, in the past, largely due to the lack of appropriate screening models, but recent developments have established such models and have provided evidence that tumor cell migration works as a surrogate for metastasis formation. Herein we deliver on several examples a rationale for not only testing novel cancer drugs by use of these screening assays, but also reconsider established drugs even of other fields of indication. Full article
(This article belongs to the Special Issue Signal Transduction 2016)
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Open AccessFeature PaperReview
MIRO GTPases in Mitochondrial Transport, Homeostasis and Pathology
Received: 3 December 2015 / Revised: 22 December 2015 / Accepted: 24 December 2015 / Published: 31 December 2015
Cited by 16 | Viewed by 3382 | PDF Full-text (720 KB) | HTML Full-text | XML Full-text
Abstract
The evolutionarily-conserved mitochondrial Rho (MIRO) small GTPase is a Ras superfamily member with three unique features. It has two GTPase domains instead of the one found in other small GTPases, and it also has two EF hand calcium binding domains, which allow Ca [...] Read more.
The evolutionarily-conserved mitochondrial Rho (MIRO) small GTPase is a Ras superfamily member with three unique features. It has two GTPase domains instead of the one found in other small GTPases, and it also has two EF hand calcium binding domains, which allow Ca2+-dependent modulation of its activity and functions. Importantly, it is specifically associated with the mitochondria and via a hydrophobic transmembrane domain, rather than a lipid-based anchor more commonly found in other small GTPases. At the mitochondria, MIRO regulates mitochondrial homeostasis and turnover. In metazoans, MIRO regulates mitochondrial transport and organization at cellular extensions, such as axons, and, in some cases, intercellular transport of the organelle through tunneling nanotubes. Recent findings have revealed a myriad of molecules that are associated with MIRO, particularly the kinesin adaptor Milton/TRAK, mitofusin, PINK1 and Parkin, as well as the endoplasmic reticulum-mitochondria encounter structure (ERMES) complex. The mechanistic aspects of the roles of MIRO and its interactors in mitochondrial homeostasis and transport are gradually being revealed. On the other hand, MIRO is also increasingly associated with neurodegenerative diseases that have roots in mitochondrial dysfunction. In this review, I discuss what is currently known about the cellular physiology and pathophysiology of MIRO functions. Full article
(This article belongs to the Special Issue Regulation and Function of Small GTPases)
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