Please wait a moment until all data is loaded. This message will disappear when all data is loaded.
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
malfunction
-
enzyme knockdown in C2C12 myotubes results in a concurrent increase in Sox6 protein levels and a decrease of Myh7 transcription
malfunction
-
enzyme knockdown inhibits thioredoxin-interacting protein degradation and results in a subsequent increase in cardiomyocyte apoptosis
malfunction
-
enzyme knockdown inhibits thioredoxin-interacting protein degradation and results in a subsequent increase in cardiomyocyte apoptosis
physiological function
depletion of ubiquitin-protein ligase HECTD3 leads to multipolar spindle formation
physiological function
E3 ligase AIP2 positively regulates T-cell activation. Ectopic expression of AIP2 in mouse primary T cells enhances their proliferation and interleukin-2 production by suppressing the apoptosis of T cells. AIP2 interacts with and promotes ubiquitin-mediated degradation of EGR2, a zinc finger transcription factor that has been found to regulate Fas ligand expression during activation-induced T-cell death. Suppression of AIP2 expression by small RNA interference upregulates EGR2, inhibits EGR2 ubiquitination and Fas ligand expression, and enhances the apoptosis of T cells
physiological function
isoform UPL5 T-DNA insertion lines show the same senescence phenotype as transcription factor WRKY53 over-expressers. Over-expression of WRKY53 in the upl5 background enhances the accelerated senescence phenotype of WRKY53 over-expressers
physiological function
NEDD4-like ubiquitin protein ligase NEDL1 cooperates with p53 to induce apoptosis. During cisplatin -mediated apoptosis in neuroblastoma SH-SY5Y cells, p53 is induced to accumulate in association with an increase in expression levels of NEDL1. Enforced expression of NEDL1 results in a decrease in number of G418-resistant colonies in SH-SY5Y and U2OS cells bearing wild-type p53, whereas NEDL1 had undetectable effect on p53-deficient H1299 and SAOS-2 cells. Enforced expression of NEDL1 increases the number of U2OS cells with sub-G1 DNA content. NEDL1 binds to the COOH-terminal region of p53 and has an ability to enhance the transcriptional activity of p53. Small interfering RNA-mediated knockdown of the endogenous NEDL1 confers the resistance of U2OS cells to adriamycin. NEDL1 enhances pro-apoptotic activity of p53 in its catalytic activity-independent manner
physiological function
RNA interference knockdown of ubiqitin ligase Nedd4-1 inhibits degradation of both epidermal grwoth factor receptor and activated Cdc42-associated tyrosine kinase, and overexpression of activated Cdc42-associated tyrosine kinase mutants that are deficient in either binding to or ubiquitination by Nedd4-1 blocks epidermal growth factor-induced degradation of epidermal growth factor receptor
physiological function
ubiquitin ligase UBR5 specifically enhances trans-activation of smooth muscle-specific promoters by the myocardin family of proteins. UBR5 significantly augments the ability of myocardin to induce expression of endogenous smooth muscle cell marker genes independent on its E3 ligase function. Depletion of endogenous UBR5 by small interfering RNA in fibroblast cells attenuates myocardin-induced smooth muscle-specific gene expression, and UBR5 knockdown in smooth muscle cells results in down-regulation of smooth muscle-specific genes. UBR5 can attenuate myocardin protein degradation resulting in increased myocardin protein expression without affecting myocardin mRNA expression. The effects of UBR5 on myocardin requires only the HECT and UBR1 domains of UBR5
physiological function
-
deletion of isoform Rsp5 or mutation of its ligase activity, blocks the nuclear export of mRNAs. Affected messenger RNAs include both total poly(A)+ mRNA and heat-shock mRNAs. Mutation of Rsp5 does not affect nuclear protein import or export. Deletion of RSP5 blocks mRNA export, even under conditions where its essential role in unsaturated fatty acids biosynthesis is bypassed. The ligase activity is required for proper mRNA export
physiological function
-
HECT-E3 ligase ETC-1 is a regulator of the cytoplasmic anaphase inhibitor securin IFY-1 level. RNAi-mediated depletion of ETC-1 stabilizes IFY-1 and cyclin B1 in post-meiosis I embryos. ETC-1 knockdown in a reduced anaphase promoting complex/cyclosome function background causes an embryonic lethal phenotype. In vitro, ETC-1 ubiquitylates IFY-1 and CYB-1 in the presence of the E2 enzyme UBC-18, which functions in pharyngeal development. UBC-18 plays a distinct role together with ETC-1 in regulating the cytoplasmic level of IFY-1 during meiosis
physiological function
HECTD3 depletion can sensitize cancer cells to extrinsic apoptotic stimuli. HECTD3 inhibits TNF-related apoptosis-inducing ligand-induced caspase-8 cleavage in an E3 ligase activity-dependent manner. Mutation of the caspase-8 ubiquitination site at K215 abolishes the HECTD3 protection from TNF-related apoptosis-inducing ligand-induced cleavage
physiological function
in a temperature-sensitive mutant strain of isoform Rsp5, ubiquitin is limiting. Reduced synthesis of ubiquitin appears to contribute to ubiquitin depletion. In a wildtype strain upon heat-shock, transient inhibition of general protein synthesis is observed. Wildtype cells quickly recover from this transient arrest, the Rsp5 mutant cells remain arrested
physiological function
-
isoform HectD1 promotes the adenomatous polyposis coli-axin interaction to negatively regulate Wnt signaling. Knockdown of HectD1 diminishes adenomatous polyposis coli ubiquitylation, disrupts the adenomatous polyposis coli-axin interaction, and augments Wnt3a-induced beta-catenin stabilization and signaling
physiological function
-
isoform Herc4 expression promotes scaffold protein Sav ubiquitylation and degradation, while Herc4 depletion stabilises Sav. Sav-binding protein Hpo reduces Sav/Herc4 interaction in a kinase-dependent manner
physiological function
isoform NEDD4L induces Dvl2 polyubiquitination and targets Dvl2 for proteasomal degradation, thereby regulating the cellular beta-catenin level and Rac1, RhoA, and JNK activities
physiological function
isoform TRIP12 catalyzes in vitro ubiquitination of ubiquitin fusion degradation substrates in conjunction with E1, E2, and E4 enzymes. Knockdown of TRIP12 stabilizes artificial ubiquitin fusion degradation substrates and physiological substrate, mutant ubiquitin UBB+1. TRIP12 knockdown reduces UBB+1-induced cell death in human neuroblastoma cells. Complementation of TRIP12 knockdown cells with the TRIP12 HECT domain mostly restores efficient degradation of ubiquitin fusion degradation substrates. The TRIP12 HECT domain directs ubiquitination of ubiquitin fusion degradation substrates in vitro and can be specifically cross-linked to the ubiquitin moiety of the substrates in vivo. A mutant ubiquitin that cannot be conjugated to other proteins is a substrate of the TRIP12 HECT domain both in vivo and in vitro
physiological function
silencing of endogenous isoform Nedd4 increases the cellular substrate Spry2 content and attenuates fibroblast growth factor-elicited ERK1/2. Mnk2 kinase silencing decreases Spry2-Nedd4 interactions and also augments the ability of Spry2 to inhibit fibroblast growth factor signaling
physiological function
T-DNA disruptions of the UPL3 locus do not affect overall growth and morphology, but display aberrant trichome morphology. Many mutant trichomes contain five or more branches instead of three branches. Mutant trichoimes often undergo an additional round of endoreplication resulting in enlarged nuclei with ploidy levels of up to 64C. Mutant plants are hypersensitive to gibberellic acid-3. The phenotype of upl3 mutants is similar to that of kaktus, a set of trichome mutants with supernumerary branches. UPL3 mutants and kaktus-2 are allelic with kaktus-2 plants harboring a splice-site mutation within the UPL3-transcribed region
physiological function
-
ubiquitin ligase Smurf2 is required for the spindle checkpoint. Smurf2 localizes to the centrosome, mitotic midbody, and centromeres. Smurf2 depletion or the expression of a catalytically inactive Smurf2 results in misaligned and lagging chromosomes, premature anaphase onset, and defective cytokinesis. Smurf2 inactivation prevents nocodazole-treated cells from accumulating cyclin B and securin and prometaphase arrest. The silencing of Cdc20 in Smurf2-depleted cells restores mitotic accumulation of cyclin B and securin. Smurf2 depletion results in enhanced polyubiquitination and degradation of Mad2, a critical checkpoint effector. Mad2 is mislocalized in Smurf2-depleted cells
physiological function
-
the enzyme targets thioredoxin-interacting protein for ubiquitin-proteasome degradation in cardiomyocytes and ameliorates reactive oxygen species-induced cardiotoxicity through the thioredoxin system. The enzyme protects cardiac remodeling, cardiac function, and survival rate in myocardial infarction
physiological function
-
the enzyme targets thioredoxin-interacting protein for ubiquitin-proteasome degradation in cardiomyocytes and ameliorates reactive oxygen species-induced cardiotoxicity through the thioredoxin system. The enzyme protects cardiac remodeling, cardiac function, and survival rate in myocardial infarction
physiological function
-
the enzyme targets transcription factor Sox6 for proteasomal degradation and affects fiber type-specific gene expression in muscle cells
physiological function
the enzyme targets transcription factor Sox6 for proteasomal degradation and affects fiber type-specific gene expression in muscle cells
physiological function
Ehrlichia chaffeensis tandem repeat protein TRP120 is posttranslationally modified by ubiquitin. Ubiquitination occurs through intrinsic and host-mediated HECT ligase activity. HECT E3 ubiquitin ligase, Nedd4L, interacts with TRP120 during infection and also mediates TRP120 ubiquitination. Nedd4L knockdown results in the reduction of TRP120 ubiquitination, decreases ehrlichial infection, and reduces recruitment of TRP120-interacting host protein, PCGF5, to ehrlichial inclusions. TRP120-mediated PCGF5 polyubiquitination is associated with a reduction in PCGF5 levels. Inhibition of ubiquitination with small molecules also significantly decreases ehrlichial infection
physiological function
-
Ehrlichia chaffeensis tandem repeat protein TRP120 is posttranslationally modified by ubiquitin. Ubiquitination occurs through intrinsic and host-mediated HECT ligase activity. The C-terminal region of TRP120 harbors a functional HECT E3 ligase domain with a conserved catalytic site. TRP120 autoubiquitination occurs in vitro in the presence of host UbcH5b/c E2 enzymes. Human HECT E3 ubiquitin ligase, Nedd4L, interacts with TRP120 during infection and also mediates TRP120 ubiquitination. Nedd4L knockdown results in the reduction of TRP120 ubiquitination, decreases ehrlichial infection, and reduces recruitment of TRP120-interacting host protein, PCGF5, to ehrlichial inclusions. TRP120-mediated PCGF5 polyubiquitination is associated with a reduction in PCGF5 levels. Inhibition of ubiquitination with small molecules also significantly decreases ehrlichial infection
physiological function
HECT E3 ligase adopts an autoinhibited state, in which its multiple WW domains sequester HECT using a multi-lock mechanism. Removing WW2 or WW34 leads to a partial activation of WWP1. The multi-lock regulation mechanism is conserved in WWP2 and Itch, whereas in Nedd4/4 L and Smurf2, a variant version of the multi-lock autoinhibition mode is utilized
physiological function
HUWE1 is a ubiquitin ligase for substrates bearing unshielded, hydrophobic segments. Many endogenous HUWE1 substrates form multi-protein complexes that function in the nucleus although HUWE1 itself is cytoplasmically localized. Inhibition of nuclear entry enhances HUWE1-mediated ubiquitination and degradation
physiological function
inactivation of ubiquitin ligase HectPH1 is sufficient to reconstitute the parental phenotype of mutants defective in the TORC2 Pia subunit, which are impaired in chemotaxis and development. HectPH1 deletion rescues both chemotactic cell polarity and the underlying PKB phosphorylation and kinase activity of mutants defective in the TORC2 Pia subunit
physiological function
loss of Ubr-5 function suppresses defects caused by reduced signaling via Notch-type receptors GLP-1 or LIN-12. Ubr-5 mutations do not suppress embryonic or larval lethality associated with mutations in downstream transcription factor, LAG-1. In the gonad, Ubr-5 acts in the receiving cells (germ cells) to limit GLP-1 signaling activity. Ubr-5 acts redundantly with the F-box component of SCFSEL-10 E3 ubiquitin-ligase SEL-10 to limit Notch signaling in certain tissues
physiological function
-
monomeric NEDD4L catalyzes only HECT ubiquitin thioester formation and monoubiquitination, whereas polyubiquitin chain assembly requires NEDD4L oligomerization and sites 1 and 2 to function in trans
physiological function
mutating the catalytic cysteine or deleting the entire HECT domain (amino acids 758-1068) results in loss of UBE3B's ubiquitylation activity. Knockdown of UBE3B in human cells induces changes in mitochondrial morphology and physiology, a decrease in mitochondrial volume, and a severe suppression of cellular proliferation
physiological function
NEDD4 ligase activation critically requires a substantial array of clustered PY motifs. Soluble protein substrates and adaptors such as alpha-arrestins, even with multiple PY elements, cannot activate ligase activity efficiently. Polymerization or membrane tethering of these substrates dramatically increases the ligase activity both in vivo and in vitro. Aggregation of luciferase-containing substrates upon heat shock has a similar effect and can also expose cryptic PY elements in the substrates
physiological function
Smurf2 mediates [D-Ala2,NMePhe4,Gly5-ol]-enkephalin (DAMGO, an agonist of MOR1)-induced MOR1 ubiquitination and degradation. DAMGO decreases MOR1 levels in the ubiquitin-proteasome system. MOR1 is modified by a Lys48-linked polyubiquitin chain. Overexpression of Smurf2 induces MOR1 ubiquitination and accelerates DAMGO-induced MOR1 degradation, whereas downregulation of Smurf2 attenuates MOR1 degradation. DAMGO increases lung epithelial cell migration and proliferation, and the effect is attenuated by overexpressing Smurf2
physiological function
the Huwe1 HECT domain prioritizes K6- and K48-polyubiquitin chains and does not interact with ubiquitin in a non-covalent manner. The architecture of the C-lobe-ubiquitin intermediate is conserved between Huwe1 and Smurf2 and involves a reorientation of the very C-terminal residues. The individual sequence composition of the Huwe1 C-terminal tail modulates ubiquitination activity, without affecting thioester formation
physiological function
ubiquitin ligase Tom1 contributes to the turnover of Spo12, a component of the Cdc14 early anaphase release network, in G2/M phase. Tom1 and Spo12 interact. Overexpression of Spo12 is cytotoxic in the absence of Tom1. In S phase, Spo12 is degraded even in the absence of Tom1 and Cdh1
physiological function
-
isoform Herc4 expression promotes scaffold protein Sav ubiquitylation and degradation, while Herc4 depletion stabilises Sav. Sav-binding protein Hpo reduces Sav/Herc4 interaction in a kinase-dependent manner
-