Ubiquitin-Protein Ligases/metabolism* ; Proteolysis ; Biological Products ; Ligands

Lipids droplets are organelles that store neutral lipids and are closely related to lipid accumulation. Long chain acyl-coenzyme A synthetase 3 (ACSL3) is a lipid droplet-associated protein mainly distributed in the cell membrane, endoplasmic reticulum, and intracellular lipid droplets, and its distribution depends on cell type and fatty acid supply. ACSL3 is a key regulator of fatty acid metabolism that is closely related to intracellular lipid accumulation, and plays an important role in various pathophysiological processes such as lipid droplet synthesis and lipid metabolism, cellular inflammation, and ferroptosis. This paper mainly reviews the role of ACSL3 in lipid synthesis, ferroptosis, and inflammatory response, with focus on the mechanism of its role in lipid accumulation in atherosclerosis, and provides new ideas for exploring potential therapeutic targets in atherosclerotic diseases.
Humans ; Atherosclerosis ; Coenzyme A Ligases/metabolism* ; Endoplasmic Reticulum/metabolism* ; Fatty Acids/metabolism* ; Lipid Metabolism

Parkinson's disease (PD) is a common neurodegenerative disorder associated with aging. Great progresses have been made toward understanding the pathogenesis over the past decades. It seems that both genetic factors and environmental factors contribute to PD, while the precise pathogenesis still remains unknown. Recently, increasing evidence has suggested that autophagy dysregulation is closely related to PD. Dysregulation of the autophagic pathways has been observed in the brains of PD patients or in animal models of PD, and a number of PD-associated proteins, such as a-synuclein, Parkin and PINK1, were found to involve in autophagy, suggesting a link between autophagy and pathogenesis of PD. In this review, we summarized the role of PD-associated proteins in autophagy pathways. In addition, we described the efficacy of autophagy-modulating compounds in PD models and discussed promising strategies for PD therapy.
Animals ; Autophagy ; Humans ; Parkinson Disease ; physiopathology ; Protein Kinases ; metabolism ; Ubiquitin-Protein Ligases ; metabolism ; alpha-Synuclein ; metabolism

Inflammatory bowel disease refers to chronic inflammatory disorders that affect the gastrointestinal tract. Ubiquitination is an important protein post-translational modification. In recent years, the research of ubiquitination-deubiquitination system in the development of inflammatory bowel disease has become a hot spot. Up to now, the E3 ubiquitin ligases such as ring finger protein 183 (RNF183), RNF20, Itch and A20 were well studied in inflammatory bowel disease. RNF183 promotes the activation of the NF-κB pathway by increasing the ubiquitination and degradation of IκBα; RNF20 drives histone H2B monoubiquitylation, downregulates a panel of inflammation-associated genes; Itch inhibits IL-17-mediated colon inflammation by retinoid acid related orphan receptor γt ubiquitination; A20 has ubiquitinating-deubiquitinating activity to regulates colon inflammation. This article reviews the role and regulatory mechanism of RNF183, RNF20, Itch and A20 in the pathogenesis of inflammatory bowel disease.
Histones ; metabolism ; Humans ; Inflammatory Bowel Diseases ; physiopathology ; NF-kappa B ; metabolism ; Ubiquitin-Protein Ligases ; metabolism ; Ubiquitination

OBJECTIVE: To explore the interaction between BCL2-associated athanogene 5 (BAG5) and Parkin protein,and the regulatory mechanism of BAG5 protein on the level of Parkin protein. METHODS: We performed GST pull-down assay to identify which domain of PINK1 interacted with Parkin, and generated different deletions of BAG5 to identify the domains. Chase time experiment was done to determine the effect of co-regulation of BAG5 protein on the ubiquitination. We further examined the possible interaction between Parkin and PINK1 in 293A cells by co-immunoprecipitation method. RESULTS: BAG5 directly interacted with the Parkin, and all the 4 BAG domains interacted with the Parkin. BAG5 stabilized the Parkin by interfering its degradation via the ubiquitin-mediated proteasomal pathway. CONCLUSION BAG5 directly interacts with the Parkin, and BAG5 stabilizes the Parkin via the ubiquitin-mediated proteasomal pathway.
Adaptor Proteins, Signal Transducing ; metabolism ; Humans ; Parkinson Disease ; metabolism ; Protein Binding ; Ubiquitin-Protein Ligases ; metabolism ; Ubiquitination

Proteolysis targeting chimera (PROTAC) refers to heterobifunctional small molecules that can simultaneously bind an E3 ubiquitin ligase and a target protein, enabling specific degradation of the target protein with the aid of the ubiquitin proteasome system. At present, most PROTAC drugs are in the clinical trial stage, and the ligands are mainly non-covalent compounds. PROTAC drugs have the advantage of overcoming drug resistance and degrading "undruggable" target proteins, but non-covalent ligands could lead to the hook effect that undermines drug efficacy. With its own advantages, covalent ligands can avoid the occurrence of this phenomenon, which is of great help to the development of PROTAC. This review summarizes the progress in preclinical and clinical research and application of PROTAC molecules targeting three different classes of protein targets, including intranuclear, transmembrane, and cytosolic proteins. We also offer perspective discussions to provide research ideas and references for the future development of PROTAC.
Proteolysis ; Proteolysis Targeting Chimera ; Proteasome Endopeptidase Complex/metabolism* ; Ubiquitin-Protein Ligases/metabolism* ; Proteins/metabolism* ; Ligands

OBJECTIVETo confirm the activity of non structural protein 1 (NSP1) of Rotavirus (RV) as E3 ubiquitin ligase by experiments and to provide some clues for NSP1 on the pathogenic mechanisms and replication of RV.

METHODSThe whole gene and RING deleted mutation gene of NSP1 were coloned into pEGFPC1 expression plasmid, and transfected into human embryonic kidney (HEK) 293 FT cells with pBlue-Script-HA-Ubiquitin. The expression of proteins were proved by using con-focal microscope and western blotting. The ubiquination of proteins were detected by co-immunoprecite.

RESULTSThe cellular proteins of HEK293FT are ubiquinated by NSP1 protein and NSP1 protein was self-ubiquinated also.

CONCLUSIONSIt revealed that RV NSP1 had the activity of E3 ubiquitin ligase and it may play a role on the modulate mechanisms of ubiquination.

HEK293 Cells ; Humans ; Rotavirus ; enzymology ; genetics ; Ubiquitin-Protein Ligases ; metabolism ; Viral Nonstructural Proteins ; genetics ; metabolism

Neurodegenerative diseases are a group of chronic progressive neuronal damage disorders. The cause is unclear, most of them share a same pathological hallmark with misfold proteins accumulating in neurons. Carboxyl-terminus of Hsc70 interacting protein (CHIP) is a dual functional molecule, which has a N terminal tetratrico peptide repeat (TPR) domain that interacts with Hsc/Hsp70 complex and Hsp90 enabling CHIP to modulate the aberrant protein folding; and a C terminal U-box ubiquitin ligase domain that binds to the 26S subunit of the proteasome involved in protein degradation via ubiqutin-proteasome system. CHIP protein mediates interactions between the chaperone system and the ubiquitin-proteasome system, and plays an important role in maintaining the protein homeostasis in cells. This article reviews the molecular characteristics and physiological functions of CHIP, and its role in cellular metabolism and discusses the relationship between CHIP dysfunction and neurodegenerative diseases.
Animals ; Humans ; Neurodegenerative Diseases ; genetics ; metabolism ; Protein Binding ; Protein Folding ; Proteolysis ; Ubiquitin-Protein Ligases ; genetics ; metabolism

To explore the regulation of eIF4E, we screened the protein interacting with eIF4E from human cDNA library by using yeast two-hybrid system. Several clones interacting with eIF4E were identified. One of them was homologous with HUWE1 (HECT, UBA and WWE domain containing 1, also named as ARF-BP1, HECTH9 or HUWE1). Cell co-immunoprecipitation showed that eIF4E could bind to HUWE1 in mammalian cells. We also found that HUWE1 bearing the HECT domain is necessary for its association with eIF4E.
Animals ; Eukaryotic Initiation Factor-4E ; metabolism ; Humans ; Ubiquitin-Protein Ligases ; metabolism

Wnt signaling has emerged as a major regulator of tissue development by governing the self-renewal and maintenance of stem cells in most tissue types. As a key upstream regulator of the Wnt pathway, the transmembrane E3 ligase ZNRF3 has recently been established to play a role in negative regulation of Wnt signaling by targeting Frizzled (FZD) receptor for ubiquitination and degradation. However, the upstream regulation of ZNRF3, in particular the turnover of ZNRF3, is still unclear. Here we report that ZNRF3 is accumulated in the presence of proteasome inhibitor treatment independent of its E3-ubiquitin ligase activity. Furthermore, the Cullin 1-specific SCF complex containing β-TRCP has been identified to directly interact with and ubiquitinate ZNRF3 thereby regulating its protein stability. Similar with the degradation of β-catenin by β-TRCP, ZNRF3 is ubiquitinated by β-TRCP in both CKI-phosphorylation- and degron-dependent manners. Thus, our findings not only identify a novel substrate for β-TRCP oncogenic regulation, but also highlight the dual regulation of Wnt signaling by β-TRCP in a context-dependent manner where β-TRCP negatively regulates Wnt signaling by targeting β-catenin, and positively regulates Wnt signaling by targeting ZNRF3.
Cells, Cultured ; Humans ; Proteolysis ; Ubiquitin-Protein Ligases ; metabolism ; Ubiquitination ; beta-Transducin Repeat-Containing Proteins ; metabolism