Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P62988 (Ubiquitin)
 4,326 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nbr1, a ubiquitous kinase scaffold protein, contains a PB1, and a ubiquitin-associated (UBA) domain. We show here that the nbr1 UBA domain binds to lysine-48 and -63 linked polyubiquitin-B chains. Nbr1 also binds to the autophagic effector protein LC3-A via a novel binding site. Ubiquitin-binding, but not PB1-mediated p62/SQSTM1 interaction, is required to target nbr1 to LC3 and polyubiquitin-positive bodies. Nbr1 binds additionally to proteins implicated in ubiquitin-mediated protein turnover and vesicle trafficking: ubiquitin-specific peptidases USP8, and the endosomal transport regulator p14/Robld3. Nbr1 thus contributes to specific steps in protein turnover regulation disrupted in several hereditary human diseases.
 ...
PMID:Interactions with LC3 and polyubiquitin chains link nbr1 to autophagic protein turnover. 1942 66

Ubiquitin-positive protein aggregates are a hallmark of many degenerative diseases. Their presence can be induced by dysfunction in protein degradation pathways such as proteasome and autophagy. We now report several lines of evidence suggesting a defect in autophagy in Dictyostelium cells lacking Vmp1 (vacuole membrane protein 1), an endoplasmic reticulum (ER)-resident protein involved in pathological processes such as cancer and pancreatitis. vmp1- null cells are unable to survive starvation or undergo autophagic cell death under the appropriate inductive signals. Moreover, confocal studies using the autophagy marker Atg8 and previous transmission electron microscopy analysis showed defects in autophagosome formation. Although Vmp1 is localized in the ER, we found colocalization with Atg8 suggesting a contribution of both Vmp1 and ER in autophagosome biogenesis or maturation. Interestingly, vmp1- mutant cells showed accumulation of huge ubiquitin-positive protein aggregates containing the autophagy marker GFP-Atg8 and the putative Dictyostelium p62 homologue as described in many degenerative human diseases. The analysis of other Dictyostelium autophagic mutants (atg1-, atg5-, atg6-, atg7- and atg8-) showed a correlation in the severity of their corresponding phenotypes and the presence of ubiquitin-positive protein aggregates suggesting that the deleterious effects associated with development of these aggregates might contribute to the complex phenotypes observed in autophagy deficient mutants. Our results suggest that Vmp1 is required for the clearance of these ubiquitinated protein aggregates through autophagy and highlight a potential role for Vmp1 in protein-aggregation diseases.
 ...
PMID:Autophagy dysfunction and ubiquitin-positive protein aggregates in Dictyostelium cells lacking Vmp1. 2000 61

The goals of this study were to determine the effects of prolonged fixation time and to optimize antigen retrieval (AR) methods on immunohistochemical (IHC) staining of common neurodegenerative disease markers. A panel of commercial antibodies (Abs) to amyloid-beta, ubiquitin, p62/sequestosome, tau, and alpha-synuclein was applied to a 2-mm tissue microarray using several AR methods. The IHC outcomes were assessed in sections that included 2 types of specimens taken from 20 postmortem brains: short-term fixation of up to 70 days before paraffin embedment and long-term fixation of up to 14 years in formalin. Good amyloid-beta IHC staining was obtained with all amyloid-beta Abs applied when a formic acid AR method was used, even after 14 years of fixation. Ubiquitin immunoreactivity was also optimally labeled with this method. The p62/sequestosome IHC outcome was optimal for tissue fixed up to 10 years, but only when the p62-lck-ligand-Ab with heat AR method was used. All hyperphosphorylated tau Abs tested worked with fixation up to 10 years, in particular with the heat AR method, whereas Abs against tau isoforms RD3 and RD4 were applicable only when the fixation time was 6 months or shorter. alpha-Synuclein-immunoreactive structures were visualized up to 14 years but only by the use of Syn42-Ab after formic acid AR or after a combination of heat and formic acid methods.
 ...
PMID:The effect of prolonged fixation time on immunohistochemical staining of common neurodegenerative disease markers. 2001 Mar 4

Ubiquitin-proteasome system and autophagy are the two major mechanisms for protein degradation in eukaryotic cells. LC3, a ubiquitin-like protein, plays an essential role in autophagy through its ability to be conjugated to phosphatidylethanolamine. In this study, we discovered a novel LC3-processing activity, and biochemically purified the 20S proteasome as the responsible enzyme. Processing of LC3 by the 20S proteasome is ATP- and ubiquitin-independent, and requires both the N-terminal helices and the ubiquitin fold of LC3; addition of the N-terminal helices of LC3 to the N terminus of ubiquitin renders ubiquitin susceptible to 20S proteasomal activity. Further, the 20S proteasome processes LC3 in a stepwise manner, it first cleaves LC3 within its ubiquitin fold and thus disrupts the conjugation function of LC3; subsequently and especially at high concentrations of the proteasome, LC3 is completely degraded. Intriguingly, proteolysis of LC3 by the 20S proteasome can be inhibited by p62, an LC3-binding protein that mediates autophagic degradation of polyubiquitin aggregates in cells. Therefore, our study implicates a potential mechanism underlying interplay between the proteasomal and autophagic pathways. This study also provides biochemical evidence suggesting relevance of the controversial ubiquitin-independent proteolytic activity of the 20S proteasome.
 ...
PMID:Processing of autophagic protein LC3 by the 20S proteasome. 2006

The ubiquitin proteasome system (UPS) plays a crucial role in biological processes integral to the development of the cardiovascular system and cardiovascular diseases. The UPS prototypically recognizes specific protein substrates and places polyubiquitin chains on them for subsequent destruction by the proteasome. This system is in place to degrade not only misfolded and damaged proteins, but is essential also in regulating a host of cell signaling pathways involved in proliferation, adaptation to stress, regulation of cell size, and cell death. During the development of the cardiovascular system, the UPS regulates cell signaling by modifying transcription factors, receptors, and structural proteins. Later, in the event of cardiovascular diseases as diverse as atherosclerosis, cardiac hypertrophy, and ischemia/reperfusion injury, ubiquitin ligases and the proteasome are implicated in protecting and exacerbating clinical outcomes. However, when misfolded and damaged proteins are ubiquitinated by the UPS, their destruction by the proteasome is not always possible because of their aggregated confirmations. Recent studies have discovered how these ubiquitinated misfolded proteins can be destroyed by alternative "specific" mechanisms. The cytosolic receptors p62, NBR, and histone deacetylase 6 recognize aggregated ubiquitinated proteins and target them for autophagy in the process of "selective autophagy." Even the ubiquitination of multiple proteins within whole organelles that drive the more general macro-autophagy may be due, in part, to similar ubiquitin-driven mechanisms. In summary, the crosstalk between the UPS and autophagy highlight the pivotal and diverse roles the UPS plays in maintaining protein quality control and regulating cardiovascular development and disease.
 ...
PMID:Sent to destroy: the ubiquitin proteasome system regulates cell signaling and protein quality control in cardiovascular development and disease. 2016 43

Autophagy serves as a cell-autonomous effector mechanism of innate immunity in the cytosol. Autophagy restricts bacterial proliferation by separating bacteria from the nutrient-rich cytosol and delivering them into bactericidal autolysosomes. Autophagy also restricts inflammation by enclosing the membrane remnants of vacuoles from which bacteria have escaped. In contrast to starvation-induced autophagy, which engulfs cytosol nonspecifically, antibacterial autophagy is receptor-mediated and selective. Several distinct pathways of antibacterial autophagy have been identified recently, which can be triggered by either bacterial PAMPs, host-mediated modifications of bacteria-containing vacuoles, or cytosolic bacteria that have become decorated with ubiquitin. Ubiquitin-coated bacteria are sensed by p62, a promiscuous autophagy receptor required for the uptake of a variety of ubiquitin-marked autophagy substrates, and by NDP52, an autophagy receptor that, by associating with the immunoregulatory kinase TBK1, may serve a dedicated function in cytosolic immunity.
 ...
PMID:How cells deploy ubiquitin and autophagy to defend their cytosol from bacterial invasion. 2119 41

Autophagy is a highly regulated intracellular process for the degradation of cytoplasmic components, especially protein aggregates and damaged organelles. It is essential for maintaining healthy cells. Impaired or deficient autophagy is believed to cause or contribute to aging and age-related disease. In this study, we investigated the effects of age on autophagy in the kidneys of 3-, 12-, and 24-month-old Fischer 344 rats. The results revealed that autophagy-related gene (Atg)7 was significantly downregulated in kidneys of increasing age. The protein expression level of the autophagy marker light chain 3/Atg8 exhibited a marked decline in aged kidneys. The levels of p62/SQSTM1 and polyubiquitin aggregates, representing the function of autophagy and proteasomal degradation, increased in older kidneys. The level of 8-hydroxydeoxyguanosine, a marker of mitochondrial DNA oxidative damage, was also increased in older kidneys. Analysis by transmission electron microscope demonstrated swelling and disintegration of cristae in the mitochondria of aged kidneys. These results suggest that autophagic function decreases with age in the kidneys of Fischer 344 rats, and autophagy may mediate the process of kidney aging, leading to the accumulation of damaged mitochondria.
 ...
PMID:Age-related changes in the function of autophagy in rat kidneys. 2145 1

Choline kinase is the first step enzyme for phosphatidylcholine (PC) de novo biosynthesis. Loss of choline kinase activity in muscle causes rostrocaudal muscular dystrophy (rmd) in mouse and congenital muscular dystrophy in human, characterized by distinct mitochondrial morphological abnormalities. We performed biochemical and pathological analyses on skeletal muscle mitochondria from rmd mice. No mitochondria were found in the center of muscle fibers, while those located at the periphery of the fibers were significantly enlarged. Muscle mitochondria in rmd mice exhibited significantly decreased PC levels, impaired respiratory chain enzyme activities, decreased mitochondrial ATP synthesis, decreased coenzyme Q and increased superoxide production. Electron microscopy showed the selective autophagic elimination of mitochondria in rmd muscle. Molecular markers of mitophagy, including Parkin, PINK1, LC3, polyubiquitin and p62, were localized to mitochondria of rmd muscle. Quantitative analysis shows that the number of mitochondria in muscle fibers and mitochondrial DNA copy number were decreased. We demonstrated that the genetic defect in choline kinase in muscle results in mitochondrial dysfunction and subsequent mitochondrial loss through enhanced activation of mitophagy. These findings provide a first evidence for a pathomechanistic link between de novo PC biosynthesis and mitochondrial abnormality.
 ...
PMID:Muscle choline kinase beta defect causes mitochondrial dysfunction and increased mitophagy. 2175 Jan 12

Ubiquitin (Ub) modifications are transduced by receptor proteins that use Ub-binding domains (UBDs) to recognize distinct interaction faces on the Ub surface. We report the nuclear magnetic resonance (NMR) solution structures of the A20-like zinc finger (A20 Znf) UBD of the Ub receptor ZNF216, and its complex with Ub, and show that the binding surface on Ub centered on Asp58 leaves the canonical hydrophobic Ile44 patch free to participate in additional interactions. We have modeled ternary complexes of the different families of UBDs and show that while many are expected to bind competitively to the same Ile44 surface or show steric incompatibility, other combinations (in particular, those involving the A20 Znf domain) are consistent with a single Ub moiety simultaneously participating in multiple interactions with different UBDs. We subsequently demonstrate by NMR that the A20 Znf domain of ZNF216 and the UBA domain of the p62 protein (an Ile44-binding UBD), which function in the same biological pathways, are able to form such a Ub-mediated ternary complex through independent interactions with a single Ub. This work supports an emerging concept of Ub acting as a scaffold to mediate multiprotein complex assembly.
 ...
PMID:Independent interactions of ubiquitin-binding domains in a ubiquitin-mediated ternary complex. 2192 1

Selective macroautophagy (autophagy) of ubiquitinated protein is implicated as a compensatory mechanism of the ubiquitin-proteasome system. p62/SQSTM1 is a key molecule managing autophagic clearance of polyubiquitinated proteins. However, little is known about mechanisms controlling autophagic degradation of polyubiquitinated proteins. Here, we show that the specific phosphorylation of p62 at serine 403 (S403) in its ubiquitin-associated (UBA) domain increases the affinity between UBA and polyubiquitin chain, resulting in efficiently targeting polyubiquitinated proteins in "sequestosomes" and stabilizing sequestosome structure as a cargo of ubiquitinated proteins for autophagosome entry. Casein kinase 2 (CK2) phosphorylates S403 of p62 directly. Furthermore, CK2 overexpression or phosphatase inhibition reduces the formation of inclusion bodies of the polyglutamine-expanded huntingtin exon1 fragment in a p62-dependent manner. We propose that phosphorylation of p62 at S403 regulates autophagic clearance of ubiquitinated proteins and protein aggregates that are poorly degraded by proteasomes.
 ...
PMID:Serine 403 phosphorylation of p62/SQSTM1 regulates selective autophagic clearance of ubiquitinated proteins. 2201 74


<< Previous 1 2 3 4 5 6 7 8 Next >>