scholarly journals Unzipping the Secrets of Amyloid Disassembly by the Human Disaggregase

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2745
Author(s):  
Aitor Franco ◽  
Lorea Velasco-Carneros ◽  
Naiara Alvarez ◽  
Natalia Orozco ◽  
Fernando Moro ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Accelerated Aging ◽  
Strong Relationship ◽  
Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
Class B ◽  
Associated Proteins ◽  
Global Health Problem ◽  
J Protein

Neurodegenerative diseases (NDs) are increasingly positioned as leading causes of global deaths. The accelerated aging of the population and its strong relationship with neurodegeneration forecast these pathologies as a huge global health problem in the upcoming years. In this scenario, there is an urgent need for understanding the basic molecular mechanisms associated with such diseases. A major molecular hallmark of most NDs is the accumulation of insoluble and toxic protein aggregates, known as amyloids, in extracellular or intracellular deposits. Here, we review the current knowledge on how molecular chaperones, and more specifically a ternary protein complex referred to as the human disaggregase, deals with amyloids. This machinery, composed of the constitutive Hsp70 (Hsc70), the class B J-protein DnaJB1 and the nucleotide exchange factor Apg2 (Hsp110), disassembles amyloids of α-synuclein implicated in Parkinson’s disease as well as of other disease-associated proteins such as tau and huntingtin. We highlight recent studies that have led to the dissection of the mechanism used by this chaperone system to perform its disaggregase activity. We also discuss whether this chaperone-mediated disassembly mechanism could be used to solubilize other amyloidogenic substrates. Finally, we evaluate the implications of the chaperone system in amyloid clearance and associated toxicity, which could be critical for the development of new therapies.

scholarly journals Dissimilar Appearances Are Deceptive–Common microRNAs and Therapeutic Strategies in Liver Cancer and Melanoma

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 114
Author(s):  
Lisa Linck-Paulus ◽  
Claus Hellerbrand ◽  
Anja K. Bosserhoff ◽  
Peter Dietrich
Keyword(s):  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Therapeutic Targets ◽  
Genetic Alterations ◽  
Therapeutic Strategies ◽  
The Future ◽  
Associated Proteins ◽  
Cancer Types ◽  
Novel Therapeutic Strategies

In this review, we summarize the current knowledge on miRNAs as therapeutic targets in two cancer types that were frequently described to be driven by miRNAs—melanoma and hepatocellular carcinoma (HCC). By focusing on common microRNAs and associated pathways in these—at first sight—dissimilar cancer types, we aim at revealing similar molecular mechanisms that are evolved in microRNA-biology to drive cancer progression. Thereby, we also want to outlay potential novel therapeutic strategies. After providing a brief introduction to general miRNA biology and basic information about HCC and melanoma, this review depicts prominent examples of potent oncomiRs and tumor-suppressor miRNAs, which have been proven to drive diverse cancer types including melanoma and HCC. To develop and apply miRNA-based therapeutics for cancer treatment in the future, it is essential to understand how miRNA dysregulation evolves during malignant transformation. Therefore, we highlight important aspects such as genetic alterations, miRNA editing and transcriptional regulation based on concrete examples. Furthermore, we expand our illustration by focusing on miRNA-associated proteins as well as other regulators of miRNAs which could also provide therapeutic targets. Finally, design and delivery strategies of miRNA-associated therapeutic agents as well as potential drawbacks are discussed to address the question of how miRNAs might contribute to cancer therapy in the future.

scholarly journals A J-protein is an essential subunit of the presequence translocase–associated protein import motor of mitochondria

2003 ◽  
Vol 163 (4) ◽  
pp. 707-713 ◽  
Author(s):  
Kaye N. Truscott ◽  
Wolfgang Voos ◽  
Ann E. Frazier ◽  
Maria Lind ◽  
Yanfeng Li ◽  
...  
Keyword(s):  
Membrane Protein ◽  
Protein Import ◽  
Protein Translocation ◽  
Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
The Matrix ◽  
Inner Membrane Protein ◽  
Mitochondrial Hsp70 ◽  
Essential Subunit ◽  
J Protein

Transport of preproteins into the mitochondrial matrix is mediated by the presequence translocase–associated motor (PAM). Three essential subunits of the motor are known: mitochondrial Hsp70 (mtHsp70); the peripheral membrane protein Tim44; and the nucleotide exchange factor Mge1. We have identified the fourth essential subunit of the PAM, an essential inner membrane protein of 18 kD with a J-domain that stimulates the ATPase activity of mtHsp70. The novel J-protein (encoded by PAM18/YLR008c/TIM14) is required for the interaction of mtHsp70 with Tim44 and protein translocation into the matrix. We conclude that the reaction cycle of the PAM of mitochondria involves an essential J-protein.

scholarly journals Rho GTPase–independent regulation of mitotic progression by the RhoGEF Net1

2013 ◽  
Vol 24 (17) ◽  
pp. 2655-2667 ◽  
Author(s):  
Sarita Menon ◽  
Wonkyung Oh ◽  
Heather S. Carr ◽  
Jeffrey A. Frost
Keyword(s):  
Molecular Mechanisms ◽  
Spindle Assembly Checkpoint ◽  
Rho Gtpase ◽  
Spindle Assembly ◽  
Nucleotide Exchange ◽  
Altered Expression ◽  
Human Cancers ◽  
Nucleotide Exchange Factor ◽  
Chromosome Congression ◽  
P21 Activated Kinase

Neuroepithelial transforming gene 1 (Net1) is a RhoA-subfamily–specific guanine nucleotide exchange factor that is overexpressed in multiple human cancers and is required for proliferation. Molecular mechanisms underlying its role in cell proliferation are unknown. Here we show that overexpression or knockdown of Net1 causes mitotic defects. Net1 is required for chromosome congression during metaphase and generation of stable kinetochore microtubule attachments. Accordingly, inhibition of Net1 expression results in spindle assembly checkpoint activation. The ability of Net1 to control mitosis is independent of RhoA or RhoB activation, as knockdown of either GTPase does not phenocopy effects of Net1 knockdown on nuclear morphology, and effects of Net1 knockdown are effectively rescued by expression of catalytically inactive Net1. We also observe that Net1 expression is required for centrosomal activation of p21-activated kinase and its downstream kinase Aurora A, which are critical regulators of centrosome maturation and spindle assembly. These results identify Net1 as a novel regulator of mitosis and indicate that altered expression of Net1, as occurs in human cancers, may adversely affect genomic stability.

scholarly journals Rac GEF Dock4 interacts with cortactin to regulate dendritic spine formation

2013 ◽  
Vol 24 (10) ◽  
pp. 1602-1613 ◽  
Author(s):  
Shuhei Ueda ◽  
Manabu Negishi ◽  
Hironori Katoh
Keyword(s):  
Dendritic Spine ◽  
Hippocampal Neurons ◽  
Molecular Mechanisms ◽  
Neuronal Development ◽  
Actin Binding ◽  
Spine Density ◽  
Nucleotide Exchange ◽  
Spine Formation ◽  
Nucleotide Exchange Factor ◽  
Important Interaction

In neuronal development, dendritic spine formation is important for the establishment of excitatory synaptic connectivity and functional neural circuits. Developmental deficiency in spine formation results in multiple neuropsychiatric disorders. Dock4, a guanine nucleotide exchange factor (GEF) for Rac, has been reported as a candidate genetic risk factor for autism, dyslexia, and schizophrenia. We previously showed that Dock4 is expressed in hippocampal neurons. However, the functions of Dock4 in hippocampal neurons and the underlying molecular mechanisms are poorly understood. Here we show that Dock4 is highly concentrated in dendritic spines and implicated in spine formation via interaction with the actin-binding protein cortactin. In cultured neurons, short hairpin RNA (shRNA)–mediated knockdown of Dock4 reduces dendritic spine density, which is rescued by coexpression of shRNA-resistant wild-type Dock4 but not by a GEF-deficient mutant of Dock4 or a truncated mutant lacking the cortactin-binding region. On the other hand, knockdown of cortactin suppresses Dock4-mediated spine formation. Taken together, the results show a novel and functionally important interaction between Dock4 and cortactin for regulating dendritic spine formation via activation of Rac.

Signalling to actin: role of C3G, a multitasking guanine-nucleotide-exchange factor

2011 ◽  
Vol 31 (4) ◽  
pp. 231-244 ◽  
Author(s):  
Vegesna Radha ◽  
Aninda Mitra ◽  
Kunal Dayma ◽  
Kotagiri Sasikumar
Keyword(s):  
Current Knowledge ◽  
Neurite Growth ◽  
Guanine Nucleotide Exchange Factor ◽  
Small Gtpases ◽  
Cell Junctions ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Exchange Factor ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor

C3G (Crk SH3-domain-binding guanine-nucleotide-releasing factor) is a ubiquitously expressed member of a class of molecules called GEFs (guanine-nucleotide-exchange factor) that activate small GTPases and is involved in pathways triggered by a variety of signals. It is essential for mammalian embryonic development and many cellular functions in adult tissues. C3G participates in regulating functions that require cytoskeletal remodelling such as adhesion, migration, maintenance of cell junctions, neurite growth and vesicle traffic. C3G is spatially and temporally regulated to act on Ras family GTPases Rap1, Rap2, R-Ras, TC21 and Rho family member TC10. Increased C3G protein levels are associated with differentiation of various cell types, indicating an important role for C3G in cellular differentiation. In signalling pathways, C3G serves functions dependent on catalytic activity as well as protein interaction and can therefore integrate signals necessary for the execution of more than one cellular function. This review summarizes our current knowledge of the biology of C3G with emphasis on its role as a transducer of signals to the actin cytoskeleton. Deregulated C3G may also contribute to pathogenesis of human disorders and therefore could be a potential therapeutic target.

scholarly journals Inclusion Formation and Toxicity of the ALS Protein RGNEF and Its Association with the Microtubule Network

2020 ◽  
Vol 21 (16) ◽  
pp. 5597 ◽  
Author(s):  
Sonja E. Di Gregorio ◽  
Kathryn Volkening ◽  
Michael J. Strong ◽  
Martin L. Duennwald
Keyword(s):  
Functional Characterization ◽  
Heterozygous Mutation ◽  
Nucleotide Exchange ◽  
Microtubule Network ◽  
Cytoplasmic Inclusions ◽  
Mammalian Cell Lines ◽  
Ubiquitin System ◽  
Nucleotide Exchange Factor ◽  
Associated Proteins ◽  
Split Ubiquitin

The Rho guanine nucleotide exchange factor (RGNEF) protein encoded by the ARHGEF28 gene has been implicated in the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Biochemical and pathological studies have shown that RGNEF is a component of the hallmark neuronal cytoplasmic inclusions in ALS-affected neurons. Additionally, a heterozygous mutation in ARHGEF28 has been identified in a number of familial ALS (fALS) cases that may give rise to one of two truncated variants of the protein. Little is known about the normal biological function of RGNEF or how it contributes to ALS pathogenesis. To further explore RGNEF biology we have established and characterized a yeast model and characterized RGNEF expression in several mammalian cell lines. We demonstrate that RGNEF is toxic when overexpressed and forms inclusions. We also found that the fALS-associated mutation in ARGHEF28 gives rise to an inclusion-forming and toxic protein. Additionally, through unbiased screening using the split-ubiquitin system, we have identified RGNEF-interacting proteins, including two ALS-associated proteins. Functional characterization of other RGNEF interactors identified in our screen suggest that RGNEF functions as a microtubule regulator. Our findings indicate that RGNEF misfolding and toxicity may cause impairment of the microtubule network and contribute to ALS pathogenesis.

scholarly journals Gulp1 controls Eph/ephrin trogocytosis and is important for cell rearrangements during development

2019 ◽  
Vol 218 (10) ◽  
pp. 3455-3471 ◽  
Author(s):  
Jingyi Gong ◽  
Thomas N. Gaitanos ◽  
Olivia Luu ◽  
Yunyun Huang ◽  
Louise Gaitanos ◽  
...  
Keyword(s):  
Embryonic Development ◽  
Molecular Mechanisms ◽  
Cultured Cells ◽  
Protein Complexes ◽  
Adaptor Protein ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Guanine Nucleotide Exchange ◽  
Protein Clusters ◽  
Nucleotide Exchange Factor

Trogocytosis, in which cells nibble away parts of neighboring cells, is an intercellular cannibalism process conserved from protozoa to mammals. Its underlying molecular mechanisms are not well understood and are likely distinct from phagocytosis, a process that clears entire cells. Bi-directional contact repulsion induced by Eph/ephrin signaling involves transfer of membrane patches and full-length Eph/ephrin protein complexes between opposing cells, resembling trogocytosis. Here, we show that the phagocytic adaptor protein Gulp1 regulates EphB/ephrinB trogocytosis to achieve efficient cell rearrangements of cultured cells and during embryonic development. Gulp1 mediates trogocytosis bi-directionally by dynamic engagement with EphB/ephrinB protein clusters in cooperation with the Rac-specific guanine nucleotide exchange factor Tiam2. Ultimately, Gulp1’s presence at the Eph/ephrin cluster is a prerequisite for recruiting the endocytic GTPase dynamin. These results suggest that EphB/ephrinB trogocytosis, unlike other trogocytosis events, uses a phagocytosis-like mechanism to achieve efficient membrane scission and engulfment.

scholarly journals A NUMB–EFA6B–ARF6 recycling route controls apically restricted cell protrusions and mesenchymal motility

2018 ◽  
Vol 217 (9) ◽  
pp. 3161-3182 ◽  
Author(s):  
Martina Zobel ◽  
Andrea Disanza ◽  
Francesca Senic-Matuglia ◽  
Michel Franco ◽  
Ivan Nicola Colaluca ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Negative Regulator ◽  
Migration And Invasion ◽  
Nucleotide Exchange ◽  
Cellular Processes ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
Endocytic Protein ◽  
Membrane Protrusions

The endocytic protein NUMB has been implicated in the control of various polarized cellular processes, including the acquisition of mesenchymal migratory traits through molecular mechanisms that have only been partially defined. Here, we report that NUMB is a negative regulator of a specialized set of understudied, apically restricted, actin-based protrusions, the circular dorsal ruffles (CDRs), induced by either PDGF or HGF stimulation. Through its PTB domain, NUMB binds directly to an N-terminal NPLF motif of the ARF6 guanine nucleotide exchange factor, EFA6B, and promotes its exchange activity in vitro. In cells, a NUMB–EFA6B–ARF6 axis regulates the recycling of the actin regulatory cargo RAC1 and is critical for the formation of CDRs that mark the acquisition of a mesenchymal mode of motility. Consistently, loss of NUMB promotes HGF-induced cell migration and invasion. Thus, NUMB negatively controls membrane protrusions and the acquisition of mesenchymal migratory traits by modulating EFA6B–ARF6 activity.

scholarly journals Disassembly of Tau fibrils by the human Hsp70 disaggregation machinery generates small seeding-competent species

2020 ◽  
Vol 295 (28) ◽  
pp. 9676-9690 ◽  
Author(s):  
Eliana Nachman ◽  
Anne S. Wentink ◽  
Karine Madiona ◽  
Luc Bousset ◽  
Taxiarchis Katsinelos ◽  
...  
Keyword(s):  
Protein Homeostasis ◽  
Nucleotide Exchange ◽  
Cell Culture Model ◽  
Nucleotide Exchange Factor ◽  
Culture Model ◽  
Class B ◽  
The Cost ◽  
Human Hsp70 ◽  
Tau Fibrils

The accumulation of amyloid Tau aggregates is implicated in Alzheimer's disease (AD) and other tauopathies. Molecular chaperones are known to maintain protein homeostasis. Here, we show that an ATP-dependent human chaperone system disassembles Tau fibrils in vitro. We found that this function is mediated by the core chaperone HSC70, assisted by specific cochaperones, in particular class B J-domain proteins and a heat shock protein 110 (Hsp110)-type nucleotide exchange factor (NEF). The Hsp70 disaggregation machinery processed recombinant fibrils assembled from all six Tau isoforms as well as Sarkosyl-resistant Tau aggregates extracted from cell cultures and human AD brain tissues, demonstrating the ability of the Hsp70 machinery to recognize a broad range of Tau aggregates. However, the chaperone activity released monomeric and small oligomeric Tau species, which induced the aggregation of self-propagating Tau conformers in a Tau cell culture model. We conclude that the activity of the Hsp70 disaggregation machinery is a double-edged sword, as it eliminates Tau amyloids at the cost of generating new seeds.

scholarly journals EFA6 in Axon Regeneration, as a Microtubule Regulator and as a Guanine Nucleotide Exchange Factor

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1325
Author(s):  
Gilberto Gonzalez ◽  
Lizhen Chen
Keyword(s):  
Molecular Mechanisms ◽  
Axon Regeneration ◽  
Calcium Influx ◽  
Nucleotide Exchange ◽  
Exchange Factor ◽  
Transcriptional Reprogramming ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
Cytoskeleton Reorganization ◽  
Target Molecules

Axon regeneration after injury is a conserved biological process that involves a large number of molecular pathways, including rapid calcium influx at injury sites, retrograde injury signaling, epigenetic transition, transcriptional reprogramming, polarized transport, and cytoskeleton reorganization. Despite the numerous efforts devoted to understanding the underlying cellular and molecular mechanisms of axon regeneration, the search continues for effective target molecules for improving axon regeneration. Although there have been significant historical efforts towards characterizing pro-regenerative factors involved in axon regeneration, the pursuit of intrinsic inhibitors is relatively recent. EFA6 (exchange factor for ARF6) has been demonstrated to inhibit axon regeneration in different organisms. EFA6 inhibition could be a promising therapeutic strategy to promote axon regeneration and functional recovery after axon injury. This review summarizes the inhibitory role on axon regeneration through regulating microtubule dynamics and through affecting ARF6 (ADP-ribosylation factor 6) GTPase-mediated integrin transport.

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