Page last updated: 2024-10-24

retrograde protein transport, ER to cytosol

Definition

Target type: biologicalprocess

The directed movement of unfolded or misfolded proteins from the endoplasmic reticulum to the cytosol through the translocon. [PMID:11994744]

Retrograde protein transport from the endoplasmic reticulum (ER) to the cytosol is a critical process that ensures proper cellular function and homeostasis. This pathway is primarily responsible for the retrieval of misfolded or unassembled proteins from the ER lumen back to the cytosol for degradation or refolding. This process is tightly regulated and involves several key components:

1. **Recognition of misfolded proteins:** Chaperone proteins within the ER lumen, such as BiP (binding immunoglobulin protein), recognize misfolded proteins. BiP binds to unfolded proteins and prevents their aggregation, potentially hindering proper folding.

2. **Translocation to the cytosol:** Misfolded proteins are then targeted for translocation back to the cytosol via the Sec61 translocon, a protein channel embedded in the ER membrane. This process involves the protein's N-terminus being exposed to the cytosolic side of the ER membrane.

3. **Ubiquitination:** Once in the cytosol, the misfolded proteins undergo ubiquitination, a process that involves the attachment of ubiquitin molecules to the protein. Polyubiquitination, the attachment of multiple ubiquitin molecules, serves as a signal for proteasomal degradation.

4. **Proteasomal degradation:** Ubiquitinated proteins are recognized by the proteasome, a large multi-protein complex responsible for degrading tagged proteins. The proteasome breaks down the misfolded protein into smaller peptides, preventing their accumulation and potential toxicity.

5. **ER-associated protein degradation (ERAD):** The entire process of retrograde transport from the ER to the cytosol for degradation is known as ERAD. This pathway is crucial for maintaining ER homeostasis, preventing the accumulation of misfolded proteins that can disrupt ER function and lead to cellular stress.

This process ensures that proteins that are unable to fold properly in the ER are removed from the secretory pathway and degraded, ultimately contributing to the overall health and functionality of the cell.'
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Proteins (2)

ProteinDefinitionTaxonomy
Transitional endoplasmic reticulum ATPaseA transitional endoplasmic reticulum ATPase that is encoded in the genome of human. [PRO:DNx, UniProtKB:P55072]Homo sapiens (human)
EndoplasminAn endoplasmin that is encoded in the genome of human. [PRO:DAN]Homo sapiens (human)

Compounds (28)

CompoundDefinitionClassesRoles
clotrimazoleconazole antifungal drug;
imidazole antifungal drug;
imidazoles;
monochlorobenzenes
antiinfective agent;
environmental contaminant;
xenobiotic
adenosine diphosphateAdenosine Diphosphate: Adenosine 5'-(trihydrogen diphosphate). An adenine nucleotide containing two phosphate groups esterified to the sugar moiety at the 5'-position.adenosine 5'-phosphate;
purine ribonucleoside 5'-diphosphate
fundamental metabolite;
human metabolite
2-chloroadenosine5-chloroformycin A: structure given in first sourcepurine nucleoside
adenosinequinquefolan B: isolated from roots of Panax quinquefolium L.; RN not in Chemline 10/87; RN from Toxlitadenosines;
purines D-ribonucleoside
analgesic;
anti-arrhythmia drug;
fundamental metabolite;
human metabolite;
vasodilator agent
adenosine-5'-carboxylic acidpurine nucleoside
adenosine 5'-carboxamideadenosine 5'-carboxamide: structure
5'-n-methylcarboxamideadenosine5'-N-methylcarboxamideadenosine: RN given refers to (beta-D)-isomer
n-methyladenosineN-methyladenosine: is a inhibitor of cell differentiation

N(6)-methyladenosine : A methyladenosine compound with one methyl group attached to N(6) of the adenine nucleobase.
methyladenosine
ethyl adenosine-5'-carboxylateethyl adenosine-5'-carboxylate: potent vasoactive substance; RN given refers to parent cpd
adenosine 5'-phosphoramidateadenosine 5'-phosphoramidate : The phosphoramadite analogue of AMP.organic phosphoramidateMycoplasma genitalium metabolite
adenosine-5'-(n-ethylcarboxamide)Adenosine-5'-(N-ethylcarboxamide): A stable adenosine A1 and A2 receptor agonist. Experimentally, it inhibits cAMP and cGMP phosphodiesterase activity.

N-ethyl-5'-carboxamidoadenosine : A derivative of adenosine in which the 5'-hydroxymethyl group is replaced by an N-ethylcarboxamido group.
adenosines;
monocarboxylic acid amide
adenosine A1 receptor agonist;
adenosine A2A receptor agonist;
antineoplastic agent;
EC 3.1.4.* (phosphoric diester hydrolase) inhibitor;
vasodilator agent
Methylenedioxycinnamic acidhydroxycinnamic acid
3,4-methylenedioxy-beta-nitrostyrene3,4-methylenedioxy-beta-nitrostyrene: tyrosine kinase inhibitor that prevents platelet glycoprotein IIb/IIIa activation; structure in first source
4-(4-(4-chloro-phenyl)thiazol-2-ylamino)phenolsubstituted aniline
adenosine-5'-(N-propyl)carboxamideadenosine-5'-(N-propyl)carboxamide : A monocarboxylic acid amide that is the propyl amide of adenosine 5'-carboxylic acid.adenosines;
monocarboxylic acid amide
1-aminoadenosine1-aminoadenosine: structure
9h-purine-9-propanamine, 6-amino-8-((6-iodo-1,3-benzodioxol-5-yl)thio)-n-(1-methylethyl)-9H-purine-9-propanamine, 6-amino-8-((6-iodo-1,3-benzodioxol-5-yl)thio)-N-(1-methylethyl)-: an epichaperome (purine-scaffold) inhibitor; structure in first source
5'-amino-5'-deoxyadenosine
n-cyclopropyl adenosine-5'-carboxamide
ec 144EC 144: structure in first source
at 13387(2,4-dihydroxy-5-isopropylphenyl)-(5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl)methanone: structure in first source

onalespib : A member of the class of isoindoles that is isoindole in which the amino group has been acylated by a 2,4-dihydroxy-5-isopropylbenzoyl group and in which position 5 of the isoidole moiety has been substituted by a (4-methylpiperazin-1-yl)methyl group. A second-generation Hsp90 inhibitor.
benzamides;
isoindoles;
N-alkylpiperazine;
resorcinols;
tertiary carboxamide
antineoplastic agent;
Hsp90 inhibitor
cnf 20242-aminopurines;
aromatic ether;
organochlorine compound;
pyridines
antineoplastic agent;
Hsp90 inhibitor
snx 2112SNX 2112: an orally available small molecule Hsp90 inhibitor; structure in first source
ML240ML240 : A member of the class of quinazolines that is quinazoline which is substituted at positions 2, 5 and 8 by 2-amino-1H-benzimidazol-1-yl, benzylnitrilo and methoxy groups, respectively. It is a ATP-competetive inhibitor of AAA ATPase p97, also known as valosin-containing protein (VCP).aromatic amine;
aromatic ether;
benzimidazoles;
primary amino compound;
quinazolines;
secondary amino compound
antineoplastic agent
tas-116
ganciclovir2-aminopurines;
oxopurine
antiinfective agent;
antiviral drug
ver 52296luminespib : A monocarboxylic acid amide obtained by formal condensation of the carboxy group of 5-(2,4-dihydroxy-5-isopropylphenyl)-4-[4-(morpholin-4-ylmethyl)phenyl]-1,2-oxazole-3-carboxylic acid with the amino group of ethylamine.aromatic amide;
isoxazoles;
monocarboxylic acid amide;
morpholines;
resorcinols
angiogenesis inhibitor;
antineoplastic agent;
Hsp90 inhibitor
sta 9090ring assembly;
triazoles