TRIM/RBCC, a novel class of ‘single protein RING finger’ E3 ubiquitin ligases

BioEssays ◽  
2005 ◽  
Vol 27 (11) ◽  
pp. 1147-1157 ◽  
Author(s):  
Germana Meroni ◽  
Graciana Diez-Roux
Keyword(s):  
Ring Finger ◽  
Ubiquitin Ligases ◽  
E3 Ubiquitin Ligases ◽  
Single Protein

scholarly journals Comprehensive Analysis of E3 Ubiquitin Ligases Reveals Ring Finger Protein 223 as a Novel Oncogene Activated by KLF4 in Pancreatic Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Lei Feng ◽  
Jieqing Wang ◽  
Jianmin Zhang ◽  
Jingfang Diao ◽  
Longguang He ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Transcriptional Activation ◽  
Prognostic Significance ◽  
Ring Finger ◽  
Ubiquitin Ligases ◽  
The Cancer Genome Atlas ◽  
Differentially Expressed ◽  
E3 Ubiquitin Ligases ◽  
E3 Ligases ◽  
Elevated Expression

Pancreatic cancer is one of the major malignancies and causes of mortality worldwide. E3 ubiquitin–protein ligases transfer activated ubiquitin from ubiquitin-conjugating enzymes to protein substrates and confer substrate specificity in cancer. In this study, we first downloaded data from The Cancer Genome Atlas pancreatic adenocarcinoma dataset, acquired all 27 differentially expressed genes (DEGs), and identified genomic alterations. Then, the prognostic significance of DEGs was analyzed, and eight DEGs (MECOM, CBLC, MARCHF4, RNF166, TRIM46, LONRF3, RNF39, and RNF223) and two clinical parameters (pathological N stage and T stage) exhibited prognostic significance. RNF223 showed independent significance as an unfavorable prognostic marker and was chosen for subsequent analysis. Next, the function of RNF223 in the pancreatic cancer cell lines ASPC-1 and PANC-1 was investigated, and RNF223 silencing promoted pancreatic cancer growth and migration. To explore the potential targets and pathways of RNF223 in pancreatic cancer, quantitative proteomics was applied to analyze differentially expressed proteins, and metabolism-related pathways were primarily enriched. Finally, the reason for the elevated expression of RNF223 was analyzed, and KLF4 was shown to contribute to the increased expression of RNF233. In conclusion, this study comprehensively analyzed the clinical significance of E3 ligases. Functional assays revealed that RNF223 promotes cancer by regulating cell metabolism. Finally, the elevated expression of RNF223 was attributed to KLF4-mediated transcriptional activation. This study broadens our knowledge regarding E3 ubiquitin ligases and signal transduction and provides novel markers and therapeutic targets in pancreatic cancer.

scholarly journals HECT and RING finger families of E3 ubiquitin ligases at a glance

2012 ◽  
Vol 125 (3) ◽  
pp. 531-537 ◽  
Author(s):  
M. B. Metzger ◽  
V. A. Hristova ◽  
A. M. Weissman
Keyword(s):  
Ring Finger ◽  
Ubiquitin Ligases ◽  
E3 Ubiquitin Ligases

scholarly journals Functional Significance of the E3 Ubiquitin Ligases in Disease and Therapeutics

2021 ◽  
Author(s):  
Julius Tieroyaare Dongdem ◽  
Cletus Adiyaga Wezena
Keyword(s):  
Therapeutic Potential ◽  
Protein Complexes ◽  
Ring Finger ◽  
Ubiquitin Ligases ◽  
E3 Ubiquitin Ligases ◽  
Phd Finger ◽  
E3 Ligases ◽  
Cellular Processes ◽  
Future Drug ◽  
Ubiquitin Conjugating Enzyme

E3 ubiquitin ligases of which there are >600 putative in humans, constitute a family of highly heterogeneous proteins and protein complexes that are the ultimate enzymes responsible for the recruitment of an ubiquitin loaded E2 ubiquitin-conjugating enzyme, recognise the appropriate protein substrate and directly or indirectly transfer the ubiquitin load onto the substrate. The aftermath of an E3 ligase activity is usually the formation of an isopeptide bond between the free carboxylate group of ubiquitin’s C-terminal Gly76 and an ε-amino group of the substrate’s Lys, even though non-canonical ubiquitylation on non-amine groups of target proteins have been observed. E3 ligases are grouped into four distinct families: HECT, RING-finger/U-box, RBR and PHD-finger. E3 ubiquitin ligases play critical roles in subcellular signalling cascades in eukaryotes. Dysfunctional E3 ubiquitin ligases therefore tend to inflict dramatic effects on human health and may result in the development of various diseases including Parkinson’s, Amyotrophic Lateral Sclerosis, Alzheimer’s, cancer, etc. Being regulators of numerous cellular processes, some E3 ubiquitin ligases have become potential targets for therapy. This chapter will present a comprehensive review of up-to-date findings in E3 ligases, their role in the pathology of disease and therapeutic potential for future drug development.

scholarly journals Identification and characterization of Fbxl22, a novel skeletal muscle atrophy-promoting E3 ubiquitin ligase

2020 ◽  
Vol 319 (4) ◽  
pp. C700-C719 ◽  
Author(s):  
David C. Hughes ◽  
Leslie M. Baehr ◽  
Julia R. Driscoll ◽  
Sarah A. Lynch ◽  
David S. Waddell ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Splice Variant ◽  
Splice Variants ◽  
Ring Finger ◽  
Ubiquitin Ligases ◽  
Skeletal Muscle Atrophy ◽  
E3 Ubiquitin Ligases ◽  
Muscle Mass Loss

Muscle-specific E3 ubiquitin ligases have been identified in muscle atrophy-inducing conditions. The purpose of the current study was to explore the functional role of F-box and leucine-rich protein 22 (Fbxl22), and a newly identified splice variant (Fbxl22–193), in skeletal muscle homeostasis and neurogenic muscle atrophy. In mouse C2C12 muscle cells, promoter fragments of the Fbxl22 gene were cloned and fused with the secreted alkaline phosphatase reporter gene to assess the transcriptional regulation of Fbxl22. The tibialis anterior muscles of male C57/BL6 mice (12–16 wk old) were electroporated with expression plasmids containing the cDNA of two Fbxl22 splice variants and tissues collected after 7, 14, and 28 days. Gastrocnemius muscles of wild-type and muscle-specific RING finger 1 knockout (MuRF1 KO) mice were electroporated with an Fbxl22 RNAi or empty plasmid and denervated 3 days posttransfection, and tissues were collected 7 days postdenervation. The full-length gene and novel splice variant are transcriptionally induced early (after 3 days) during neurogenic muscle atrophy. In vivo overexpression of Fbxl22 isoforms in mouse skeletal muscle leads to evidence of myopathy/atrophy, suggesting that both are involved in the process of neurogenic muscle atrophy. Knockdown of Fbxl22 in the muscles of MuRF1 KO mice resulted in significant additive muscle sparing 7 days after denervation. Targeting two E3 ubiquitin ligases appears to have a strong additive effect on protecting muscle mass loss with denervation, and these findings have important implications in the development of therapeutic strategies to treat muscle atrophy.

scholarly journals E3 ubiquitin ligases LNX1 and LNX2 are major regulators of the presynaptic glycine transporter GlyT2

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
A. de la Rocha-Muñoz ◽  
E. Núñez ◽  
E. Arribas-González ◽  
B. López-Corcuera ◽  
C. Aragón ◽  
...  
Keyword(s):  
Synaptic Vesicles ◽  
Ring Finger ◽  
Ubiquitin Ligases ◽  
Sudden Infant Death ◽  
Limiting Current ◽  
Sudden Infant ◽  
E3 Ubiquitin Ligases ◽  
Loss Of Function ◽  
Glycine Transporter ◽  
Glycinergic Neurotransmission

Abstract The neuronal glycine transporter GlyT2 is an essential regulator of glycinergic neurotransmission that recaptures glycine in presynaptic terminals to facilitate transmitter packaging in synaptic vesicles. Alterations in GlyT2 expression or activity result in lower cytosolic glycine levels, emptying glycinergic synaptic vesicles and impairing neurotransmission. Lack of glycinergic neurotransmission caused by GlyT2 loss-of-function mutations results in Hyperekplexia, a rare neurological disease characterized by generalized stiffness and motor alterations that may cause sudden infant death. Although the importance of GlyT2 in pathology is known, how this transporter is regulated at the molecular level is poorly understood, limiting current therapeutic strategies. Guided by an unbiased screening, we discovered that E3 ubiquitin ligase Ligand of Numb proteins X1/2 (LNX1/2) modulate the ubiquitination status of GlyT2. The N-terminal RING-finger domain of LNX1/2 ubiquitinates a cytoplasmic C-terminal lysine cluster in GlyT2 (K751, K773, K787 and K791), and this process regulates the expression levels and transport activity of GlyT2. The genetic deletion of endogenous LNX2 in spinal cord primary neurons causes an increase in GlyT2 expression and we find that LNX2 is required for PKC-mediated control of GlyT2 transport. This work identifies, to our knowledge, the first E3 ubiquitin-ligases acting on GlyT2, revealing a novel molecular mechanism that controls presynaptic glycine availability. Providing a better understanding of the molecular regulation of GlyT2 may help future investigations into the molecular basis of human disease states caused by dysfunctional glycinergic neurotransmission, such as hyperekplexia and chronic pain.

Sign in / Sign up

Export Citation Format

Share Document