Preferred Label : Endoplasmic Reticulum Degradation Pathway;
NCIt synonyms : ER Degradation Pathway;
NCIt related terms : ER-associated degradation (ERAD) Pathway;
Alternative definition : BIOCARTA: The endoplasmic reticulum (ER) of the cell operates a quality control system
that identifies misfolded proteins, transports them into the cytoplasm and then targets
them for degradation by the proteasome. Aberrant protein degradation is the mechanism
underlying many diseases, including cystic fibrosis and heritable forms of lung and
liver disease. The pathways that orchestrate the destruction of aberrant proteins
are collectively termed ER-associated degradation (ERAD). Most of the proteins synthesized
in the ER are cotranslationally modified with N (asparagine)-linked glycans by addition
of triglycosylated, branched oligosaccharides at asparagines residues. Rapid glucose
trimming by ER glucosidases generates monoglucosylated N-glycans (Glc0-3Man9GlcNAc2).
Productive folding of the polypeptides to which the glycans are attached requires
the services of an ER lectin chaperone called calnexin (CNX) that recognize the Glc1Man9GlcNAc2
oligosaccharide and assists the folding of newly synthesized glycoproteins. Because
the half-time of monoglucose in the nascent glycoproteins is about 2 min, the protein
should be repeatedly reglycosylated by UDP-glucose: glycoprotein glucosyltransferase
(UGGT) resulting in association with CNX. Next, the mannose residue from the middle
branch of the Man9GlcNAc2 oligosaccharide is removed by ER -mannosidase I, then correctly
folded glycoproteins bearing Man8GlcNAc2 isomer B (Man8B form) are transported out
of the ER to the Golgi apparatus. If the native structure of the glycoprotein cannot
be achieved it is retained in the ER. When substrates are released from CNX by glucosidase
II, they may be transferred to one of 2 pathways: EDEM for degradation or UUGT for
reentry into CNX cycle. A glycoprotein with permanent structural defects is modified
by the slow-acting enzyme ER mannosidase I. This enzyme attaches Man8 glycans to misfolded
glycoproteins and in so doing generates a signal that results in ER-associated glycoprotein
degradation (GERAD). A glycoprotein with a glycan in the form Glc0-3Man8GlcNAc2 is
released from the calnexin cycle, recognised by a mannosidase- like protein EDEM and
dislocated from the ER to the cytosol. Here the protein binds to the glycan-specific
F box protein Fbx2 and is targeted to the SCF-Fbx2-type E3 ubiquitin ligase complex.
This results in the protein being polyubiquitinated. The protein is subsequently deglycosylated
by a cytosolic peptide N-glycanase (PNGase) that is closely associated with the ubiquitin
ligase complex and/or the 19S lid of the proteasome. Finally, the ubiquitinated, deglycosylated
protein is degraded by the proteasome. (This definition may be outdated - see the
DesignNote.);
NCIt note : The BIOCARTA Definition (ALT_DEFINITION) for this pathway concept was provided by
BioCarta. This property was not created by, nor is it maintained by the NCI Thesaurus
staff. Additionally, BioCarta is no longer updating its pathway data; thus, the BIOCARTA
Definition might be outdated or inaccurate. Please see the Terms and Conditions for
Use at http://www.biocarta.com/.;
Biocarta ID : h_eradPathway;
Origin ID : C39288;
UMLS CUI : C1512129;
Semantic type(s)
has_gene_product_element
pathway_has_gene_element