Page last updated: 2024-10-24

positive regulation of ERAD pathway

Definition

Target type: biologicalprocess

Any process that activates or increases the frequency, rate or extent of ERAD pathway. [GO_REF:0000058, GOC:bf, GOC:PARL, GOC:TermGenie]

The ERAD pathway, short for Endoplasmic Reticulum-Associated Degradation, is a crucial quality control system for protein folding in the endoplasmic reticulum (ER). It is a tightly regulated process that ensures proper protein folding and removes misfolded or unassembled proteins from the ER lumen. Positive regulation of the ERAD pathway involves a cascade of events that enhance the identification, extraction, and degradation of misfolded proteins.

The initial step involves the recognition of misfolded proteins by chaperones like BiP, calnexin, and calreticulin. These chaperones assist in the proper folding of proteins and prevent aggregation. However, when a protein fails to fold correctly, these chaperones can also act as sensors, initiating the ERAD pathway.

Once a misfolded protein is recognized, it is ubiquitinated, a process involving the attachment of a ubiquitin molecule. This ubiquitination tag serves as a signal for the ERAD machinery to extract the misfolded protein from the ER lumen. The extraction is facilitated by a complex of proteins known as the ERAD translocon, which acts as a protein channel.

The ubiquitinated protein is then transferred to the cytoplasm, where it is degraded by the proteasome. The proteasome is a large protein complex responsible for breaking down misfolded or damaged proteins. This proteolytic activity ensures that misfolded proteins are eliminated, preventing their accumulation and potential toxicity.

Factors that positively regulate the ERAD pathway include:

* **Increased levels of chaperones**: Higher concentrations of chaperones like BiP enhance the recognition and binding of misfolded proteins.
* **Increased activity of ubiquitin ligases**: These enzymes promote the attachment of ubiquitin to misfolded proteins, marking them for degradation.
* **Activation of transcription factors**: Stress-responsive transcription factors, such as ATF6 and XBP1, can upregulate the expression of ERAD components, enhancing the pathway's efficiency.
* **Post-translational modifications**: Modifications like phosphorylation can regulate the activity of ERAD components, fine-tuning the pathway.

In summary, positive regulation of the ERAD pathway is essential for maintaining proper protein folding within the ER and ensuring the removal of misfolded proteins to prevent cellular dysfunction and stress.'
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Proteins (2)

ProteinDefinitionTaxonomy
Ubiquitin carboxyl-terminal hydrolase 13A ubiquitin carboxyl-terminal hydrolase 13 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q92995]Homo sapiens (human)
Nuclear factor erythroid 2-related factor 2A nuclear factor erythroid 2-related factor 2 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q16236]Homo sapiens (human)

Compounds (23)

CompoundDefinitionClassesRoles
melatoninacetamides;
tryptamines
anticonvulsant;
central nervous system depressant;
geroprotector;
hormone;
human metabolite;
immunological adjuvant;
mouse metabolite;
radical scavenger
sulforaphanesulforaphane : An isothiocyanate having a 4-(methylsulfinyl)butyl group attached to the nitrogen.

sulforaphane: from Cardaria draba L.
isothiocyanate;
sulfoxide
antineoplastic agent;
antioxidant;
EC 3.5.1.98 (histone deacetylase) inhibitor;
plant metabolite
dimethylformamideDimethylformamide: A formamide in which the amino hydrogens are replaced by methyl groups.

N,N-dimethylformamide : A member of the class of formamides that is formamide in which the amino hydrogens are replaced by methyl groups.
formamides;
volatile organic compound
geroprotector;
hepatotoxic agent;
polar aprotic solvent
iberinisothiocyanate;
sulfoxide
apoptosis inducer;
plant metabolite;
quorum sensing inhibitor
oleanolic acidhydroxy monocarboxylic acid;
pentacyclic triterpenoid
plant metabolite
2-tert-butylhydroquinone2-tert-butylhydroquinone : A member of the class of hydroquinones in which one of the ring hydrogens of hydroquinone is replaced by a tert-butyl group.

2-tert-butylhydroquinone: an anticarcinogenic and chemopreventive agent
hydroquinonesfood antioxidant
brusatolbrusatol: quassinoid from B. javanica; structuretriterpenoid
hei 712organofluorine compound;
quinolone
2-(5-Chlorobenzo[b]thiophen-3-yl)acetic acid1-benzothiophenes
alyssinsulfoxide
bardoxolone methylmethyl 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oate: structure in first sourcecyclohexenones
resveratroltrans-resveratrol : A resveratrol in which the double bond has E configuration.resveratrolantioxidant;
phytoalexin;
plant metabolite;
quorum sensing inhibitor;
radical scavenger
dimethyl fumaratediester;
enoate ester;
methyl ester
antipsoriatic;
immunomodulator
(1e,4e)-1,5-bis(2-methoxyphenyl)penta-1,4-dien-3-one
curcumincurcumin : A beta-diketone that is methane in which two of the hydrogens are substituted by feruloyl groups. A natural dyestuff found in the root of Curcuma longa.

Curcumin: A yellow-orange dye obtained from tumeric, the powdered root of CURCUMA longa. It is used in the preparation of curcuma paper and the detection of boron. Curcumin appears to possess a spectrum of pharmacological properties, due primarily to its inhibitory effects on metabolic enzymes.
aromatic ether;
beta-diketone;
diarylheptanoid;
enone;
polyphenol
anti-inflammatory agent;
antifungal agent;
antineoplastic agent;
biological pigment;
contraceptive drug;
dye;
EC 1.1.1.205 (IMP dehydrogenase) inhibitor;
EC 1.1.1.21 (aldehyde reductase) inhibitor;
EC 1.1.1.25 (shikimate dehydrogenase) inhibitor;
EC 1.6.5.2 [NAD(P)H dehydrogenase (quinone)] inhibitor;
EC 1.8.1.9 (thioredoxin reductase) inhibitor;
EC 2.7.10.2 (non-specific protein-tyrosine kinase) inhibitor;
EC 3.5.1.98 (histone deacetylase) inhibitor;
flavouring agent;
food colouring;
geroprotector;
hepatoprotective agent;
immunomodulator;
iron chelator;
ligand;
lipoxygenase inhibitor;
metabolite;
neuroprotective agent;
nutraceutical;
radical scavenger
umi-77UMI-77: an Mcl-1 inhibitor; structure in first source
2,6-bis(2,5-dimethoxybenzylidene)cyclohexanone2,6-bis(2,5-dimethoxybenzylidene)cyclohexanone: an anti-inflammatory agent that down-regulates cyclooxygenase-2 expression; structure in first source
strigolstrigol : A strigolactone in which the tricyclic lactone moiety bears a hydroxy substitutuent at the position para to the gem-dimethyl group.

strigol: a strigolactone from roots of various PLANTS; it stimulates seed germination of parasitic STRIGA and OROBANCHE; structure in first source
indenofuran;
secondary alcohol;
strigolactone
hylin
6-methylsulfinylhexyl isothiocyanate6-(Methylsulfinyl)hexyl isothiocyanate: showed a dose-dependent inhibition of LPS-induced nitric oxide (NO), iNOS mRNA and protein.sulfoxide
dimethoxycurcumindimethoxycurcumin: has antineoplsatic activity; structure in first source
spautin-1
(1S,2R)-2-[[(1S)-1-[(1,3-dioxo-2-isoindolyl)methyl]-3,4-dihydro-1H-isoquinolin-2-yl]-oxomethyl]-1-cyclohexanecarboxylic acidLH601A: inhibits the interaction between KEAP1 and NRF2; structure in first sourcephthalimides