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 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 FUNDC1 interacts with FBXL2 to govern mitochondrial integrity and cardiac function through an IP3R3-dependent manner in obesity

2020 ◽  
Vol 6 (38) ◽  
pp. eabc8561 ◽  
Author(s):  
Jun Ren ◽  
Mingming Sun ◽  
Hao Zhou ◽  
Amir Ajoolabady ◽  
Yuan Zhou ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Ubiquitin Ligase ◽  
High Fat Diet ◽  
Dependent Manner ◽  
Cardiac Damage ◽  
Ubiquitin Ligase Complex ◽  
F Box Protein ◽  
Trisphosphate Receptor ◽  
Type 3 ◽  
Mitochondrial Anomalies

Defective mitophagy is causally linked to obesity complications. Here, we identified an interaction between mitophagy protein FUNDC1 (FUN14 domain containing 1) and receptor subunit of human SCF (SKP1/cullin/F-box protein) ubiquitin ligase complex FBXL2 as a gatekeeper for mitochondrial Ca2+ homeostasis through degradation of IP3R3 (inositol 1,4,5-trisphosphate receptor type 3). Loss of FUNDC1 in FUNDC1−/− mice accentuated high-fat diet–induced cardiac remodeling, functional and mitochondrial anomalies, cell death, rise in IP3R3, and Ca2+ overload. Mass spectrometry and co-immunoprecipitation analyses revealed an interaction between FUNDC1 and FBXL2. Truncated mutants of Fbox (Delta-F-box) disengaged FBXL2 interaction with FUNDC1. Activation or transfection of FBXL2, inhibition of IP3R3 alleviated, whereas disruption of FBXL2 localization sensitized lipotoxicity-induced cardiac damage. FUNDC1 deficiency accelerated and decelerated palmitic acid–induced degradation of FBXL2 and IP3R3, respectively. Our data suggest an essential role for interaction between FUNDC1 and FBXL2 in preserving mitochondrial Ca2+ homeostasis and cardiac function in obese hearts.

scholarly journals Lys29-linkage of ASK1 by Skp1−Cullin 1−Fbxo21 ubiquitin ligase complex is required for antiviral innate response

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Zhou Yu ◽  
Taoyong Chen ◽  
Xuelian Li ◽  
Mingjin Yang ◽  
Songqing Tang ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Type I Interferon ◽  
Innate Immune ◽  
Type I ◽  
Innate Response ◽  
Scf Complex ◽  
Protein Ubiquitination ◽  
Ubiquitin Ligase Complex ◽  
F Box Protein ◽  
Unknown Component

Protein ubiquitination regulated by ubiquitin ligases plays important roles in innate immunity. However, key regulators of ubiquitination during innate response and roles of new types of ubiquitination (apart from Lys48- and Lys63-linkage) in control of innate signaling have not been clearly understood. Here we report that F-box only protein Fbxo21, a functionally unknown component of SCF (Skp1–Cul1–F-box protein) complex, facilitates Lys29-linkage and activation of ASK1 (apoptosis signal-regulating kinase 1), and promotes type I interferon production upon viral infection. Fbxo21 deficiency in mice cells impairs virus-induced Lys29-linkage and activation of ASK1, attenuates c-Jun N-terminal kinase (JNK) and p38 signaling pathway, and decreases the production of proinflammatory cytokines and type I interferon, resulting in reduced antiviral innate response and enhanced virus replication. Therefore Fbxo21 is required for ASK1 activation via Lys29-linkage of ASK1 during antiviral innate response, providing mechanistic insights into non-proteolytic roles of SCF complex in innate immune response.

scholarly journals FBXW7 influences murine intestinal homeostasis and cancer, targeting Notch, Jun, and DEK for degradation

2011 ◽  
Vol 208 (2) ◽  
pp. 295-312 ◽  
Author(s):  
Roya Babaei-Jadidi ◽  
Ningning Li ◽  
Anas Saadeddin ◽  
Bradley Spencer-Dene ◽  
Anett Jandke ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Rna Splicing ◽  
Early Time ◽  
Cancer Targeting ◽  
Wild Type ◽  
Intestinal Tumorigenesis ◽  
Time Points ◽  
Ubiquitin Ligase Complex ◽  
Tumor Tissues ◽  
F Box Protein

The Fbxw7 (F-box/WD repeat–containing protein 7; also called CDC4, Sel10, Ago, and Fbw7) component of the SCF (Skp1/Cullin/F-box protein) E3 ubiquitin ligase complex acts as a tumor suppressor in several tissues and targets multiple transcriptional activators and protooncogenes for ubiquitin-mediated degradation. To understand Fbxw7 function in the murine intestine, in this study, we specifically deleted Fbxw7 in the murine gut using Villin-Cre (Fbxw7ΔG). In wild-type mice, loss of Fbxw7 in the gut altered homeostasis of the intestinal epithelium, resulted in elevated Notch and c-Jun expression, and induced development of adenomas at 9–10 mo of age. In the context of APC (adenomatous polyposis coli) deficiency (ApcMin/+ mice), loss of Fbxw7 accelerated intestinal tumorigenesis and death and promoted accumulation of β-catenin in adenomas at late but not early time points. At early time points, Fbxw7 mutant tumors showed accumulation of the DEK protooncogene. DEK expression promoted cell division and altered splicing of tropomyosin (TPM) RNA, which may also influence cell proliferation. DEK accumulation and altered TPM RNA splicing were also detected in FBXW7 mutant human colorectal tumor tissues. Given their reduced lifespan and increased incidence of intestinal tumors, ApcMin/+Fbxw7ΔG mice may be used for testing carcinogenicity and drug screening.

scholarly journals Major components in the KARRIKIN INSENSITIVE2-ligand signaling pathway are conserved in the liverwort, Marchantia polymorpha

2020 ◽  
Author(s):  
Yohei Mizuno ◽  
Aino Komatsu ◽  
Shota Shimazaki ◽  
Xiaonan Xie ◽  
Kimitsune Ishizaki ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Ubiquitin Ligase ◽  
Common Ancestor ◽  
Marchantia Polymorpha ◽  
Wild Type ◽  
Knock Out ◽  
Ubiquitin Ligase Complex ◽  
The Common ◽  
F Box Protein ◽  
And Control

AbstractKARRIKIN INSENSITIVE2 (KAI2) was first identified in Arabidopsis thaliana as a receptor of karrikin, a smoke-derived germination stimulant. KAI2 is also considered a receptor of an unidentified endogenous molecule called the KAI2-ligand (KL). Upon KAI2 activation, signals are transmitted through degradation of D53/SMXL proteins via ubiquitination by a Skp-Cullin-F-box (SCF) E3 ubiquitin ligase complex. All components in the KL signaling pathway exist in the liverwort Marchantia polymorpha, namely MpKAI2A and MpKAI2B, MpMAX2 encoding the F-box protein, and MpSMXL, indicating that the signaling pathway became functional in the common ancestor of bryophytes and seed plants. Genetic analysis using knock-out mutants of these KL signaling genes, produced using the CRISPR system, indicated that MpKAI2A, MpMAX2 and MpSMXL act in the same genetic pathway and control early gemma growth. Introduction of MpSMXLd53, in which a domain required for degradation is mutated, into wild-type plants caused phenotypes resembling those of the Mpkai2a and Mpmax2 mutants. In addition, Citrine fluorescence was detected in tobacco cells transiently transformed with the 35S:MpSMXL-Citrine gene construct and treated with MG132, a proteasome inhibitor. On the other hand, introduction of 35S:MpSMXLd53-Citrine conferred Citrine fluorescence without MG132 treatment. These findings imply that MpSMXL is subjected to degradation, and that degradation of MpSMXL is crucial for KL signaling in M. polymorpha. We also showed that MpSMXL is negatively regulated by KL signaling. Taken together, this study demonstrates that basic mechanisms in the KL signaling pathway are conserved in M. polymorpha.

scholarly journals Structural basis of the phosphorylation-independent recognition of cyclin D1 by the SCFFBXO31 ubiquitin ligase

2017 ◽  
Vol 115 (2) ◽  
pp. 319-324 ◽  
Author(s):  
Yunfeng Li ◽  
Kai Jin ◽  
Eric Bunker ◽  
Xiaojuan Zhang ◽  
Xuemei Luo ◽  
...  
Keyword(s):  
Cyclin D1 ◽  
Ubiquitin Ligase ◽  
Nuclear Export ◽  
D1 Protein ◽  
Genotoxic Stress ◽  
Structural Basis ◽  
Independent Manner ◽  
Functional Studies ◽  
Ubiquitin Ligase Complex ◽  
F Box Protein

Ubiquitin-dependent proteolysis of cyclin D1 is associated with normal and tumor cell proliferation and survival. The SCFFBXO31 (Skp1–Cul1–Rbx1–FBXO31) ubiquitin ligase complex mediates genotoxic stress-induced cyclin D1 degradation. Previous studies have suggested that cyclin D1 levels are maintained at steady state by phosphorylation-dependent nuclear export and subsequent proteolysis in the cytoplasm. Here we present the crystal structures of the Skp1–FBXO31 complex alone and bound to a phosphorylated cyclin D1 C-terminal peptide. FBXO31 possesses a unique substrate-binding domain consisting of two β-barrel motifs, whereas cyclin D1 binds to FBXO31 by tucking its free C-terminal carboxylate tail into an open cavity of the C-terminal FBXO31 β-barrel. Biophysical and functional studies demonstrate that SCFFBXO31 is capable of recruiting and ubiquitinating cyclin D1 in a phosphorylation-independent manner. Our findings provide a conceptual framework for understanding the substrate specificity of the F-box protein FBXO31 and the mechanism of FBXO31-regulated cyclin D1 protein turnover.

scholarly journals Wnt signalling in the development of axon, dendrites and synapses

Open Biology ◽  
2018 ◽  
Vol 8 (10) ◽  
pp. 180116 ◽  
Author(s):  
Chun-Wei He ◽  
Chien-Po Liao ◽  
Chun-Liang Pan
Keyword(s):  
Neural Development ◽  
Planar Cell Polarity ◽  
Neuronal Development ◽  
Synapse Formation ◽  
Calcium Signalling ◽  
Wnt Signalling ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation ◽  
Body Patterning ◽  
Neuronal Polarization

Wnts are a highly conserved family of secreted glycoproteins that play essential roles in the morphogenesis and body patterning during the development of metazoan species. In recent years, mounting evidence has revealed important functions of Wnt signalling in diverse aspects of neural development, including neuronal polarization, guidance and branching of the axon and dendrites, as well as synapse formation and its structural remodelling. In contrast to Wnt signalling in cell proliferation and differentiation, which mostly acts through β-catenin-dependent pathways, Wnts engage a diverse array of non-transcriptional cascades in neuronal development, such as the planar cell polarity, cytoskeletal or calcium signalling pathways. In this review, we summarize recent advances in the mechanisms of Wnt signalling in the development of axon, dendrite and synapse formation.

scholarly journals Ligand-dependent Degradation of Smad3 by a Ubiquitin Ligase Complex of ROC1 and Associated Proteins

2001 ◽  
Vol 12 (5) ◽  
pp. 1431-1443 ◽  
Author(s):  
Minoru Fukuchi ◽  
Takeshi Imamura ◽  
Tomoki Chiba ◽  
Takanori Ebisawa ◽  
Masahiro Kawabata ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Target Genes ◽  
Transforming Growth Factor ◽  
Ring Finger ◽  
Transforming Growth Factor Β ◽  
Dependent Manner ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Ligase Complex ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

Smads are signal mediators for the members of the transforming growth factor-β (TGF-β) superfamily. Upon phosphorylation by the TGF-β receptors, Smad3 translocates into the nucleus, recruits transcriptional coactivators and corepressors, and regulates transcription of target genes. Here, we show that Smad3 activated by TGF-β is degraded by the ubiquitin–proteasome pathway. Smad3 interacts with a RING finger protein, ROC1, through its C-terminal MH2 domain in a ligand-dependent manner. An E3 ubiquitin ligase complex ROC1-SCFFbw1a consisting of ROC1, Skp1, Cullin1, and Fbw1a (also termed βTrCP1) induces ubiquitination of Smad3. Recruitment of a transcriptional coactivator, p300, to nuclear Smad3 facilitates the interaction with the E3 ligase complex and triggers the degradation process of Smad3. Smad3 bound to ROC1-SCFFbw1a is then exported from the nucleus to the cytoplasm for proteasomal degradation. TGF-β/Smad3 signaling is thus irreversibly terminated by the ubiquitin–proteasome pathway.

scholarly journals Ubiquitination of exposed glycoproteins by SCFFBXO27 directs damaged lysosomes for autophagy

2017 ◽  
Vol 114 (32) ◽  
pp. 8574-8579 ◽  
Author(s):  
Yukiko Yoshida ◽  
Sayaka Yasuda ◽  
Toshiharu Fujita ◽  
Maho Hamasaki ◽  
Arisa Murakami ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Snare Proteins ◽  
Ubiquitin Ligase Complex ◽  
F Box Protein ◽  
Lysosomal Proteins ◽  
Lysosomal Protein

Ubiquitination functions as a signal to recruit autophagic machinery to damaged organelles and induce their clearance. Here, we report the characterization of FBXO27, a glycoprotein-specific F-box protein that is part of the SCF (SKP1/CUL1/F-box protein) ubiquitin ligase complex, and demonstrate that SCFFBXO27 ubiquitinates glycoproteins in damaged lysosomes to regulate autophagic machinery recruitment. Unlike F-box proteins in other SCF complexes, FBXO27 is subject to N-myristoylation, which localizes it to membranes, allowing it to accumulate rapidly around damaged lysosomes. We also screened for proteins that are ubiquitinated upon lysosomal damage, and identified two SNARE proteins, VAMP3 and VAMP7, and five lysosomal proteins, LAMP1, LAMP2, GNS, PSAP, and TMEM192. Ubiquitination of all glycoproteins identified in this screen increased upon FBXO27 overexpression. We found that the lysosomal protein LAMP2, which is ubiquitinated preferentially on lysosomal damage, enhances autophagic machinery recruitment to damaged lysosomes. Thus, we propose that SCFFBXO27 ubiquitinates glycoproteins exposed upon lysosomal damage to induce lysophagy.

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