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 PARP1-dependent recruitment of the FBXL10-RNF68-RNF2 ubiquitin ligase to sites of DNA damage controls H2A.Z loading

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Gergely Rona ◽  
Domenico Roberti ◽  
Yandong Yin ◽  
Julia K Pagan ◽  
Harrison Homer ◽  
...  
Keyword(s):  
Dna Damage ◽  
Homologous Recombination ◽  
Ubiquitin Ligase ◽  
Transcriptional Repression ◽  
Genotoxic Stress ◽  
Strand Break ◽  
Homologous Recombination Repair ◽  
Dependent Manner ◽  
Ubiquitin Ligase Complex ◽  
Recombination Repair

The mammalian FBXL10-RNF68-RNF2 ubiquitin ligase complex (FRRUC) mono-ubiquitylates H2A at Lys119 to repress transcription in unstressed cells. We found that the FRRUC is rapidly and transiently recruited to sites of DNA damage in a PARP1- and TIMELESS-dependent manner to promote mono-ubiquitylation of H2A at Lys119, a local decrease of H2A levels, and an increase of H2A.Z incorporation. Both the FRRUC and H2A.Z promote transcriptional repression, double strand break signaling, and homologous recombination repair (HRR). All these events require both the presence and activity of the FRRUC. Moreover, the FRRUC and its activity are required for the proper recruitment of BMI1-RNF2 and MEL18-RNF2, two other ubiquitin ligases that mono-ubiquitylate Lys119 in H2A upon genotoxic stress. Notably, whereas H2A.Z is not required for H2A mono-ubiquitylation, impairment of the latter results in the inhibition of H2A.Z incorporation. We propose that the recruitment of the FRRUC represents an early and critical regulatory step in HRR.

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 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 The Novel Ubiquitin Ligase Complex, SCFFbxw4, Interacts with the COP9 Signalosome in an F-Box Dependent Manner, Is Mutated, Lost and Under-Expressed in Human Cancers

PLoS ONE ◽  
2013 ◽  
Vol 8 (5) ◽  
pp. e63610 ◽  
Author(s):  
William W. Lockwood ◽  
Sahiba K. Chandel ◽  
Greg L. Stewart ◽  
Hediye Erdjument-Bromage ◽  
Levi J. Beverly
Keyword(s):  
Ubiquitin Ligase ◽  
Cop9 Signalosome ◽  
Dependent Manner ◽  
The Novel ◽  
Human Cancers ◽  
Ubiquitin Ligase Complex

scholarly journals CDK9 Is Constitutively Expressed throughout the Cell Cycle, and Its Steady-State Expression Is Independent of SKP2

2003 ◽  
Vol 23 (15) ◽  
pp. 5165-5173 ◽  
Author(s):  
Judit Garriga ◽  
Sabyasachi Bhattacharya ◽  
Joaquim Calbó ◽  
Renée M. Marshall ◽  
May Truongcao ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Ubiquitin Ligase ◽  
Proteasome Inhibitors ◽  
Elongation Factor ◽  
Dependent Manner ◽  
Protein Levels ◽  
Ubiquitin Ligase Complex ◽  
A Cell ◽  
Cycle Dependent ◽  
Interfering Rna

ABSTRACT CDK9 is a CDC2-related kinase and the catalytic subunit of the positive-transcription elongation factor b and the Tat-activating kinase. It has recently been reported that CDK9 is a short-lived protein whose levels are regulated during the cell cycle by the SCFSKP2 ubiquitin ligase complex (R. E. Kiernan et al., Mol. Cell. Biol. 21:7956-7970, 2001). The results presented here are in contrast to those observations. CDK9 protein levels remained unchanged in human cells entering and progressing through the cell cycle from G0, despite dramatic changes in SKP2 expression. CDK9 levels also remained unchanged in cells exiting from mitosis and progressing through the next cell cycle. Similarly, the levels of CDK9 protein did not change as cells exited the cell cycle and differentiated along various lineages. In keeping with these observations, the kinase activity associated with CDK9 was found to not be regulated during the cell cycle. We have also found that endogenous CDK9 is a very stable protein with a half-life (t 1/2) of 4 to 7 h, depending on the cell type. In contrast, when CDK9 is overexpressed, it is not stabilized and is rapidly degraded, with a t 1/2 of less than 1 h, depending on the level of expression. Treatment of cells with proteasome inhibitors blocked the degradation of short-lived proteins, such as p27, but did not affect the expression of endogenous CDK9. Ectopic overexpression of SKP2 led to reduction of p27 protein levels but had no effect on the expression of endogenous CDK9. Finally, downregulation of endogenous SKP2 gene expression by interfering RNA had no effect on CDK9 protein levels, whereas p27 protein levels increased dramatically. Therefore, the SCFSKP2 ubiquitin ligase does not regulate CDK9 expression in a cell cycle-dependent manner.

scholarly journals Conditional inactivation of Fbxw7 impairs cell-cycle exit during T cell differentiation and results in lymphomatogenesis

2007 ◽  
Vol 204 (12) ◽  
pp. 2875-2888 ◽  
Author(s):  
Ichiro Onoyama ◽  
Ryosuke Tsunematsu ◽  
Akinobu Matsumoto ◽  
Taichi Kimura ◽  
Ignacio Moreno de Alborán ◽  
...  
Keyword(s):  
Cell Cycle ◽  
T Cells ◽  
T Cell ◽  
Cell Lineage ◽  
Mutant Mice ◽  
Dependent Manner ◽  
Protein Subunit ◽  
Ubiquitin Ligase Complex ◽  
Conditional Inactivation ◽  
F Box Protein

Cell proliferation is strictly controlled during differentiation. In T cell development, the cell cycle is normally arrested at the CD4+CD8+ stage, but the mechanism underlying such differentiation-specific exit from the cell cycle has been unclear. Fbxw7 (also known as Fbw7, Sel-10, hCdc4, or hAgo), an F-box protein subunit of an SCF-type ubiquitin ligase complex, induces the degradation of positive regulators of the cell cycle, such as c-Myc, c-Jun, cyclin E, and Notch. FBXW7 is often mutated in a subset of human cancers. We have now achieved conditional inactivation of Fbxw7 in the T cell lineage of mice and found that the cell cycle is not arrested at the CD4+CD8+ stage in the homozygous mutant animals. The mutant mice manifested thymic hyperplasia as a result of c-Myc accumulation and eventually developed thymic lymphoma. In contrast, mature T cells of the mutant mice failed to proliferate in response to mitogenic stimulation and underwent apoptosis in association with accumulation of c-Myc and p53. These latter abnormalities were corrected by deletion of p53. Our results suggest that Fbxw7 regulates the cell cycle in a differentiation-dependent manner, with its loss resulting in c-Myc accumulation that leads to hyperproliferation in immature T cells but to p53-dependent cell-cycle arrest and apoptosis in mature T cells.

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 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 A SPOPL/Cullin-3 ubiquitin ligase complex regulates endocytic trafficking by targeting EPS15 at endosomes

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Michaela Gschweitl ◽  
Anna Ulbricht ◽  
Christopher A Barnes ◽  
Radoslav I Enchev ◽  
Ingrid Stoffel-Studer ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Ubiquitin Ligase ◽  
Mammalian Cells ◽  
Influenza A ◽  
Endocytic Trafficking ◽  
Dependent Manner ◽  
Ubiquitin Ligase Complex ◽  
Cullin 3 ◽  
Host Cell Entry ◽  
Endosome Maturation

Cullin-3 (CUL3)-based ubiquitin ligases regulate endosome maturation and trafficking of endocytic cargo to lysosomes in mammalian cells. Here, we report that these functions depend on SPOPL, a substrate-specific CUL3 adaptor. We find that SPOPL associates with endosomes and is required for both the formation of multivesicular bodies (MVBs) and the endocytic host cell entry of influenza A virus. In SPOPL-depleted cells, endosomes are enlarged and fail to acquire intraluminal vesicles (ILVs). We identify a critical substrate ubiquitinated by CUL3-SPOPL as EPS15, an endocytic adaptor that also associates with the ESCRT-0 complex members HRS and STAM on endosomes. Indeed, EPS15 is ubiquitinated in a SPOPL-dependent manner, and accumulates with HRS in cells lacking SPOPL. Together, our data indicates that a CUL3-SPOPL E3 ubiquitin ligase complex regulates endocytic trafficking and MVB formation by ubiquitinating and degrading EPS15 at endosomes, thereby influencing influenza A virus infection as well as degradation of EGFR and other EPS15 targets.

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.

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