scholarly journals The F-Box Protein CG5003 Regulates Axon Pruning and the Integrity of the Drosophila Mushroom Body

2021 ◽  
Vol 14 ◽  
Author(s):  
Mengying Yang ◽  
Yige Guo ◽  
Shuran Wang ◽  
Changyan Chen ◽  
Yung-Heng Chang ◽  
...  
Keyword(s):  
Mushroom Body ◽  
Neuronal Development ◽  
Protein Homeostasis ◽  
Axon Pruning ◽  
Cellular Processes ◽  
Synaptic Structure ◽  
F Box Protein ◽  
Associated Function ◽  
Synaptic Structures ◽  
Transcription Regulator Activity

Protein homeostasis serves as an important step in regulating diverse cellular processes underlying the function and development of the nervous system. In particular, the ubiquitination proteasome system (UPS), a universal pathway mediating protein degradation, contributes to the development of numerous synaptic structures, including the Drosophila olfactory-associative learning center mushroom body (MB), thereby affecting associated function. Here, we describe the function of a newly characterized Drosophila F-box protein CG5003, an adaptor for the RING-domain type E3 ligase (SCF complex), in MB development. Lacking CG5003 ubiquitously causes MB γ axon pruning defects and selective CG5003 expression in pan-neurons leads to both γ axon and α/β lobe abnormalities. Interestingly, change in CG5003 expression in MB neurons does not cause any abnormalities in axons, suggesting that CG5003 functions in cells extrinsic to MB to regulate its development. Mass spectrum analysis indicates that silencing CG5003 expression in all neurons affects expression levels of proteins in the cell and structural morphogenesis, transcription regulator activity, and catalytic activity. Our findings reinforce the importance of UPS and identify a new factor in regulating neuronal development as exemplified by the synaptic structure MB.

scholarly journals Skp1 Independent Function of Cdc53/Cul1 in F-box Protein Homeostasis

PLoS Genetics ◽  
2015 ◽  
Vol 11 (12) ◽  
pp. e1005727 ◽  
Author(s):  
Radhika Mathur ◽  
James L. Yen ◽  
Peter Kaiser
Keyword(s):  
Protein Homeostasis ◽  
Independent Function ◽  
F Box Protein

scholarly journals Regulation of cell cycle drivers by Cullin-RING ubiquitin ligases

2020 ◽  
Vol 52 (10) ◽  
pp. 1637-1651 ◽  
Author(s):  
Sang-Min Jang ◽  
Christophe E. Redon ◽  
Bhushan L. Thakur ◽  
Meriam K. Bahta ◽  
Mirit I. Aladjem
Keyword(s):  
Cell Cycle ◽  
Cell Division ◽  
Cell Cycle Progression ◽  
Ubiquitin Ligases ◽  
Anaphase Promoting Complex ◽  
Cycle Progression ◽  
Cellular Processes ◽  
Cellular Pathways ◽  
Regulation Of Cell Cycle ◽  
F Box Protein

Abstract The last decade has revealed new roles for Cullin-RING ubiquitin ligases (CRLs) in a myriad of cellular processes, including cell cycle progression. In addition to CRL1, also named SCF (SKP1-Cullin 1-F box protein), which has been known for decades as an important factor in the regulation of the cell cycle, it is now evident that all eight CRL family members are involved in the intricate cellular pathways driving cell cycle progression. In this review, we summarize the structure of CRLs and their functions in driving the cell cycle. We focus on how CRLs target key proteins for degradation or otherwise alter their functions to control the progression over the various cell cycle phases leading to cell division. We also summarize how CRLs and the anaphase-promoting complex/cyclosome (APC/C) ligase complex closely cooperate to govern efficient cell cycle progression.

scholarly journals Phyllopod Acts as an Adaptor Protein To Link the Sina Ubiquitin Ligase to the Substrate Protein Tramtrack

2002 ◽  
Vol 22 (19) ◽  
pp. 6854-6865 ◽  
Author(s):  
Songhui Li ◽  
Chunyan Xu ◽  
Richard W. Carthew
Keyword(s):  
Ubiquitin Ligase ◽  
Neuronal Development ◽  
Adaptor Protein ◽  
Ras Signaling ◽  
Binding Domains ◽  
Substrate Protein ◽  
Ras Activation ◽  
Ubiquitin Ligase Complex ◽  
Acid Domain ◽  
F Box Protein

ABSTRACT The RING domain protein Sina, together with Phyllopod and the F-box protein Ebi, forms a Ras-regulated E3 ubiquitin ligase complex that activates photoreceptor cell differentiation in the eye of Drosophila melanogaster. The expression of Phyllopod is induced upon Ras activation, allowing the complex to degrade the transcription repressor Tramtrack and removing its block of neuronal development in photoreceptor precursors. We show that Phyllopod functions as an adaptor in the complex, physically linking Sina with Tramtrack via separate binding domains. One 19-amino-acid domain in Phyllopod interacts with a region of Sina's SBD domain. Another domain in Phyllopod interacts with a C-terminal helix in the POZ domain of Tramtrack. This interaction is specific to the Tramtrack POZ domain and not to other POZ domain proteins present in photoreceptor precursors. Degradation of Tramtrack is dependent upon association of Sina with its cognate binding site in Phyllopod. These results illustrate how Ras signaling can modulate an E3 ligase activity not by the phosphorylation of substrate proteins but by regulating the expression of specific E3 adaptors.

scholarly journals When the chains do not break: the role of USP10 in physiology and pathology

2020 ◽  
Vol 11 (12) ◽  
Author(s):  
Udayan Bhattacharya ◽  
Fiifi Neizer-Ashun ◽  
Priyabrata Mukherjee ◽  
Resham Bhattacharya
Keyword(s):  
Complex Formation ◽  
Molecular Mechanisms ◽  
Protein Homeostasis ◽  
Post Translational Modification ◽  
Intracellular Protein ◽  
Lysosomal Degradation ◽  
Life Activity ◽  
Cellular Processes ◽  
Pathological Conditions

AbstractDeubiquitination is now understood to be as important as its partner ubiquitination for the maintenance of protein half-life, activity, and localization under both normal and pathological conditions. The enzymes that remove ubiquitin from target proteins are called deubiquitinases (DUBs) and they regulate a plethora of cellular processes. DUBs are essential enzymes that maintain intracellular protein homeostasis by recycling ubiquitin. Ubiquitination is a post-translational modification where ubiquitin molecules are added to proteins thus influencing activation, localization, and complex formation. Ubiquitin also acts as a tag for protein degradation, especially by proteasomal or lysosomal degradation systems. With ~100 members, DUBs are a large enzyme family; the ubiquitin-specific peptidases (USPs) being the largest group. USP10, an important member of this family, has enormous significance in diverse cellular processes and many human diseases. In this review, we discuss recent studies that define the roles of USP10 in maintaining cellular function, its involvement in human pathologies, and the molecular mechanisms underlying its association with cancer and neurodegenerative diseases. We also discuss efforts to modulate USPs as therapy in these diseases.

scholarly journals Drosophila microRNA-34 Impairs Axon Pruning of Mushroom Body γ Neurons by Downregulating the Expression of Ecdysone Receptor

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Yen-Wei Lai ◽  
Sao-Yu Chu ◽  
Jia-Yi Wei ◽  
Chu-Ya Cheng ◽  
Jian-Chiuan Li ◽  
...  
Keyword(s):  
Mushroom Body ◽  
Ecdysone Receptor ◽  
Axon Pruning

scholarly journals F-Box Proteins and Cancer

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1249 ◽  
Author(s):  
Kanae Yumimoto ◽  
Yuhei Yamauchi ◽  
Keiichi I. Nakayama
Keyword(s):  
Ubiquitin Ligase ◽  
Molecular Basis ◽  
Cancer Therapeutics ◽  
S Phase ◽  
Cancer Development ◽  
Tumor Promoters ◽  
Cellular Processes ◽  
Novel Targets ◽  
Scf Ubiquitin Ligase ◽  
F Box Protein

Controlled protein degradation is essential for the operation of a variety of cellular processes including cell division, growth, and differentiation. Identification of the relations between ubiquitin ligases and their substrates is key to understanding the molecular basis of cancer development and to the discovery of novel targets for cancer therapeutics. F-box proteins function as the substrate recognition subunits of S-phase kinase-associated protein 1 (SKP1)−Cullin1 (CUL1)−F-box protein (SCF) ubiquitin ligase complexes. Here, we summarize the roles of specific F-box proteins that have been shown to function as tumor promoters or suppressors. We also highlight proto-oncoproteins that are targeted for ubiquitylation by multiple F-box proteins, and discuss how these F-box proteins are deployed to regulate their cognate substrates in various situations.

scholarly journals Fbxo45 Forms a Novel Ubiquitin Ligase Complex and Is Required for Neuronal Development

2009 ◽  
Vol 29 (13) ◽  
pp. 3529-3543 ◽  
Author(s):  
Toru Saiga ◽  
Takaichi Fukuda ◽  
Masaki Matsumoto ◽  
Hirobumi Tada ◽  
Hirotaka James Okano ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Neural Development ◽  
Neuronal Development ◽  
Synapse Formation ◽  
Neuromuscular Junctions ◽  
Consensus Sequence ◽  
Ring Finger ◽  
Fiber Tracts ◽  
Ubiquitin Ligase Complex ◽  
F Box Protein

ABSTRACT Fbxo45 is an F-box protein that is restricted to the nervous system. Unlike other F-box proteins, Fbxo45 was found not to form an SCF complex as a result of an amino acid substitution in the consensus sequence for Cul1 binding. Proteomics analysis revealed that Fbxo45 specifically associates with PAM (protein associated with Myc), a RING finger-type ubiquitin ligase. Mice deficient in Fbxo45 were generated and found to die soon after birth as a result of respiratory distress. Fbxo45 − / − embryos show abnormal innervation of the diaphragm, impaired synapse formation at neuromuscular junctions, and aberrant development of axon fiber tracts in the brain. Similar defects are also observed in mice lacking Phr1 (mouse ortholog of PAM), suggesting that Fbxo45 and Phr1 function in the same pathway. In addition, neuronal migration was impaired in Fbxo45 − / − mice. These results suggest that Fbxo45 forms a novel Fbxo45-PAM ubiquitin ligase complex that plays an important role in neural development.

scholarly journals The tumor suppressor archipelago E3 ligase is required for spermatid differentiation in Drosophila testis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Viktor Vedelek ◽  
Attila L. Kovács ◽  
Gábor Juhász ◽  
Elham Alzyoud ◽  
Rita Sinka
Keyword(s):  
Tumor Suppressor ◽  
Mitochondrial Morphology ◽  
Male Sterile ◽  
Tissue Specific ◽  
Cellular Processes ◽  
Ubiquitin Ligase Complex ◽  
Drosophila Testis ◽  
Human Orthologue ◽  
F Box Protein ◽  
Multiple Abnormalities

AbstractThe human orthologue of the tumor suppressor protein FBW7 is encoded by the Drosophila archipelago (ago) gene. Ago is an F-box protein that gives substrate specificity to its SCF ubiquitin ligase complex. It has a central role in multiple biological processes in a tissue-specific manner such as cell proliferation, cellular differentiation, hypoxia-induced gene expression. Here we present a previously unknown tissue-specific role of Ago in spermatid differentiation. We identified a classical mutant of ago which is semi-lethal and male-sterile. During the characterization of ago function in testis, we found that ago plays role in spermatid development, following meiosis. We confirmed spermatogenesis defects by silencing ago by RNAi in testes. The ago mutants show multiple abnormalities in elongating and elongated spermatids, including aberration of the cyst morphology, malformed mitochondrial structures, and individualization defects. Additionally, we determined the subcellular localization of Ago protein with mCherry-Ago transgene in spermatids. Our findings highlight the potential roles of Ago in different cellular processes of spermatogenesis, like spermatid individualization, and regulation of mitochondrial morphology.

scholarly journals Axonal chemokine-like Orion induces astrocyte infiltration and engulfment during mushroom body neuronal remodeling

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ana Boulanger ◽  
Camille Thinat ◽  
Stephan Züchner ◽  
Lee G. Fradkin ◽  
Hugues Lortat-Jacob ◽  
...  
Keyword(s):  
Functional Analysis ◽  
Nervous System ◽  
Mushroom Body ◽  
Active Role ◽  
Mushroom Bodies ◽  
Axon Pruning ◽  
Neuronal Remodeling ◽  
Neuronal Signal ◽  
And Function ◽  
Fundamental Mechanism

AbstractThe remodeling of neurons is a conserved fundamental mechanism underlying nervous system maturation and function. Astrocytes can clear neuronal debris and they have an active role in neuronal remodeling. Developmental axon pruning ofDrosophilamemory center neurons occurs via a degenerative process mediated by infiltrating astrocytes. However, how astrocytes are recruited to the axons during brain development is unclear. Using an unbiased screen, we identify the gene requirement oforion, encoding for a chemokine-like protein, in the developing mushroom bodies. Functional analysis shows that Orion is necessary for both axonal pruning and removal of axonal debris. Orion performs its functions extracellularly and bears some features common to chemokines, a family of chemoattractant cytokines. We propose that Orion is a neuronal signal that elicits astrocyte infiltration and astrocyte-driven axonal engulfment required during neuronal remodeling in theDrosophiladeveloping brain.

scholarly journals Mechanosensing and the Hippo Pathway in Microglia: A Potential Link to Alzheimer’s Disease Pathogenesis?

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3144
Author(s):  
Lucrezia Bruno ◽  
Simge Karagil ◽  
Almas Mahmood ◽  
Ahmed Elbediwy ◽  
Michael Stolinski ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuronal Development ◽  
Hippo Pathway ◽  
Inflammatory Cells ◽  
Cellular Processes ◽  
Potential Link ◽  
The Central Nervous System ◽  
Sense And Respond ◽  
The Hippo Pathway

The activation of microglia, the inflammatory cells of the central nervous system (CNS), has been linked to the pathogenesis of Alzheimer’s disease and other neurodegenerative diseases. How microglia sense the changing brain environment, in order to respond appropriately, is still being elucidated. Microglia are able to sense and respond to the mechanical properties of their microenvironment, and the physical and molecular pathways underlying this mechanosensing/mechanotransduction in microglia have recently been investigated. The Hippo pathway functions through mechanosensing and subsequent protein kinase cascades, and is critical for neuronal development and many other cellular processes. In this review, we examine evidence for the potential involvement of Hippo pathway components specifically in microglia in the pathogenesis of Alzheimer’s disease. We suggest that the Hippo pathway is worth investigating as a mechanosensing pathway in microglia, and could be one potential therapeutic target pathway for preventing microglial-induced neurodegeneration in AD.

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