Abstract:Abnormal and exaggerated deposition of extracellular matrix proteins is the common feature of fibrotic diseases. The resulting fibrosis disrupts the normal architecture of the affected organs and finally leads to their dysfunction and failure. At present, there are no effective therapies for fibrotic diseases. Protein degradation via the ubiquitin-proteasome system is the major pathway for non-lysosomal proteolysis and controls many critical cellular functions including cell-cycle progression, deoxyribonucleic… Show more
“…Ubiquitin-mediated protein degradation represents the most universal mechanism for the regulation of protein availability and activity and is carried out by the ubiquitin proteasome system . Juliana et al immunoprecipitated NLRP3 and then immunoblotted for ubiquitin, revealing that NLRP3 is ubiquitinated .…”
Section: Resultsmentioning
confidence: 99%
“…Ubiquitin-mediated protein degradation represents the most universal mechanism for the regulation of protein availability and activity and is carried out by the ubiquitin proteasome system. 42 Juliana et al immunoprecipitated NLRP3 and then immunoblotted for ubiquitin, revealing that NLRP3 is ubiquitinated. 41 To investigate whether TCBQ promotes the priming of the NLRP3 inflammasome by regulating its ubiquitination, we further measured the ubiquitination status of NLRP3.…”
Section: Chemical Research In Toxicologymentioning
Our previous studies suggested that tetrachlorobenzoquinone (TCBQ) elicits pro-inflammatory activities; however, the mechanism of its toxicity toward vascular endothelial cell has not been characterized. Although TCBQ has been shown to stimulate interleukin-1 beta (IL-1β) expression, it is unknown whether TCBQ regulates post-translational IL-1β activation. Using human umbilical vein endothelial cells, we discovered that TCBQ not only promotes the expression of NOD-like receptor family, pyrin domain-containing protein 3 (NLRP3) components [composed of NLRP3, adaptor molecule apoptosis-associated speck like protein containing a caspase activation and recruitment domain (ASC), and pro-caspase 1] but also participates in priming the NLRP3 inflammasome. Activation of the NLRP3 inflammasome results in the maturation and release of IL-1β. Further experiments showed that K(+) efflux, reactive oxygen species (ROS) production, and mitochondrial DNA damage may be involved in NLRP3 inflammasome activation mediated by TCBQ. Moreover, TCBQ downregulates the ubiquitination of NLRP3, further facilitating the activation of the NLRP3 inflammasome. These results suggest that the NLRP3/IL-1β signaling pathway plays an important role in TCBQ-induced endothelial cell pro-inflammatory responses, which may point to potential therapeutic approaches against TCBQ-mediated toxicity.
“…Ubiquitin-mediated protein degradation represents the most universal mechanism for the regulation of protein availability and activity and is carried out by the ubiquitin proteasome system . Juliana et al immunoprecipitated NLRP3 and then immunoblotted for ubiquitin, revealing that NLRP3 is ubiquitinated .…”
Section: Resultsmentioning
confidence: 99%
“…Ubiquitin-mediated protein degradation represents the most universal mechanism for the regulation of protein availability and activity and is carried out by the ubiquitin proteasome system. 42 Juliana et al immunoprecipitated NLRP3 and then immunoblotted for ubiquitin, revealing that NLRP3 is ubiquitinated. 41 To investigate whether TCBQ promotes the priming of the NLRP3 inflammasome by regulating its ubiquitination, we further measured the ubiquitination status of NLRP3.…”
Section: Chemical Research In Toxicologymentioning
Our previous studies suggested that tetrachlorobenzoquinone (TCBQ) elicits pro-inflammatory activities; however, the mechanism of its toxicity toward vascular endothelial cell has not been characterized. Although TCBQ has been shown to stimulate interleukin-1 beta (IL-1β) expression, it is unknown whether TCBQ regulates post-translational IL-1β activation. Using human umbilical vein endothelial cells, we discovered that TCBQ not only promotes the expression of NOD-like receptor family, pyrin domain-containing protein 3 (NLRP3) components [composed of NLRP3, adaptor molecule apoptosis-associated speck like protein containing a caspase activation and recruitment domain (ASC), and pro-caspase 1] but also participates in priming the NLRP3 inflammasome. Activation of the NLRP3 inflammasome results in the maturation and release of IL-1β. Further experiments showed that K(+) efflux, reactive oxygen species (ROS) production, and mitochondrial DNA damage may be involved in NLRP3 inflammasome activation mediated by TCBQ. Moreover, TCBQ downregulates the ubiquitination of NLRP3, further facilitating the activation of the NLRP3 inflammasome. These results suggest that the NLRP3/IL-1β signaling pathway plays an important role in TCBQ-induced endothelial cell pro-inflammatory responses, which may point to potential therapeutic approaches against TCBQ-mediated toxicity.
“…1). There are many reports of establishing UUO in knockout mice and the roles of many cell cycle-related molecules in renal damage have been investigated in UUO kidneys [24]. Fig.…”
Section: Unilateral Ureteral Obstruction (Uuo) and Anti-thymocyte Sermentioning
S-phase kinase-associated protein 2 (Skp2) is an F-box protein component of the Skp/Cullin/F-box-type E3 ubiquitin ligase that targets several cell cycle regulatory proteins for degradation through the ubiquitin-dependent pathway. Skp2-mediated degradation of p27, a cyclin-dependent kinase inhibitor, is involved in cell cycle regulation. Tubular epithelial cell proliferation is a characteristic feature of renal damage that is apparent in the early stages of nephropathy. The p27 level is associated with the progression of renal injury, and increased Skp2 expression in progressive nephropathy is implicated in decreases of p27 expression. In Skp2−/− mice, renal damage caused by unilateral ureteral obstruction (UUO) was ameliorated by p27 accumulation, mainly in tubular epithelial cells. However, the amelioration of UUO-induced renal injury in Skp2−/− mice was prevented by p27 deficiency in Skp2−/−/p27−/− mice. These results suggest that the Skp2-mediated reduction in p27 is a pathogenic activity that occurs during the progression of nephropathy. Here, we discuss the roles of the Skp2/p27 axis and/or related signaling pathways/components in the progression of chronic nephropathy.
“…This modification is of great biological significance since it encompasses nearly all aspects of cellular events. Dysregulation in ubiquitination leads to severe consequences and human diseases, such as cancers, degenerative diseases and immune disorders [8]. This review provides overview of the enzymatic machinery mediating ubiquitination and surveys the roles of ubiquitination in regulating embryonic stem (ES) cell maintenance and cancer development.…”
Ubiquitination regulates nearly every aspect of cellular events in eukaryotes. It modifies intracellular proteins with 76-amino acid polypeptide ubiquitin (Ub) and destines them for proteolysis or activity alteration. Ubiquitination is generally achieved by a tri-enzyme machinery involving ubiquitin activating enzymes (E1), ubiquitin conjugating enzymes (E2) and ubiquitin ligases (E3). E1 activates Ub and transfers it to the active cysteine site of E2 via a transesterification reaction. E3 coordinates with E2 to mediate isopeptide bond formation between Ub and substrate protein. The E1-E2-E3 cascade can create diverse types of Ub modifications, hence effecting distinct outcomes on the substrate proteins. Dysregulation of ubiquitination results in severe consequences and human diseases. There include cancers, developmental defects and immune disorders. In this review, we provide an overview of the ubiquitination machinery and discuss the recent progresses in the ubiquitination-mediated regulation of embryonic stem cell maintenance and cancer biology.
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