Target type: biologicalprocess
Any process that stops, prevents or reduces the frequency, rate or extent of the IRE1-mediated unfolded protein response. [GO_REF:0000058, GOC:bf, GOC:PARL, GOC:TermGenie, PMID:22013210]
The unfolded protein response (UPR) is a cellular stress response that is activated in response to the accumulation of misfolded proteins in the endoplasmic reticulum (ER). IRE1 is a key component of the UPR pathway, and its activation leads to the splicing of XBP1 mRNA, which encodes a transcription factor that induces the expression of genes involved in ER protein folding and degradation. However, prolonged or excessive activation of the UPR can be detrimental to cells, leading to apoptosis. Therefore, negative regulation of the IRE1-mediated UPR is crucial for maintaining cellular homeostasis.
Several mechanisms have been identified that negatively regulate IRE1 activity:
1. **ER chaperones:** Chaperones like BiP/GRP78 bind to IRE1 and inhibit its activation. When misfolded proteins accumulate in the ER, BiP/GRP78 dissociates from IRE1, allowing it to activate.
2. **ER stress sensor:** The ER stress sensor protein, PERK, can negatively regulate IRE1 activity by phosphorylating it. This phosphorylation event can either inhibit IRE1 activity directly or indirectly by promoting its degradation.
3. **Feedback inhibition:** The spliced form of XBP1, a downstream effector of IRE1, can inhibit IRE1 activity by binding to its RNA-binding domain and blocking its interaction with its target mRNA.
4. **MicroRNAs:** Specific microRNAs have been shown to downregulate IRE1 expression and activity, thereby contributing to negative regulation of the UPR.
5. **Deubiquitinases:** Deubiquitinases can remove ubiquitin modifications from IRE1, potentially affecting its activity and stability.
6. **Protein degradation:** IRE1 can be targeted for degradation through proteasomal or lysosomal pathways, contributing to the downregulation of its activity.
These mechanisms work in concert to ensure that the UPR is appropriately activated and deactivated, preventing excessive stress and cellular dysfunction.'
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| Protein | Definition | Taxonomy |
|---|---|---|
| Endoplasmic reticulum chaperone BiP | An endoplasmic reticulum chaperone BiP that is encoded in the genome of human. [PRO:DAN] | Homo sapiens (human) |
| Compound | Definition | Classes | Roles |
|---|---|---|---|
| dichlorophen | Dichlorophen: Nontoxic laxative vermicide effective for taenia infestation. It tends to produce colic and nausea. It is also used as a veterinary fungicide, anthelmintic, and antiprotozoan. (From Merck, 11th ed.) | bridged diphenyl fungicide; diarylmethane | |
| hexachlorophene | hexachlorophene : An organochlorine compound that is diphenylmethane in which each of the phenyl groups is substituted by chlorines at positions 2, 3, and 5, and by a hydroxy group at position 6. An antiseptic that is effective against Gram-positive organisms, it is used in soaps and creams for the treatment of various skin disorders. It is also used in agriculture as an acaricide and fungicide, but is not approved for such use within the European Union. Hexachlorophene: A chlorinated bisphenol antiseptic with a bacteriostatic action against Gram-positive organisms, but much less effective against Gram-negative organisms. It is mainly used in soaps and creams and is an ingredient of various preparations used for skin disorders. (From Martindale, The Extra Pharmacopoeia, 30th ed, p797) | bridged diphenyl fungicide; polyphenol; trichlorobenzene | acaricide; antibacterial agent; antifungal agrochemical; antiseptic drug |
| triclosan | aromatic ether; dichlorobenzene; monochlorobenzenes; phenols | antibacterial agent; antimalarial; drug allergen; EC 1.3.1.9 [enoyl-[acyl-carrier-protein] reductase (NADH)] inhibitor; EC 1.5.1.3 (dihydrofolate reductase) inhibitor; fungicide; persistent organic pollutant; xenobiotic | |
| adenosine diphosphate | Adenosine 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 |
| 2,2'-methylenebis(ethyl-6-tert-butylphenol) | |||
| 2,2'-methylenebis(4-methyl-6-tert-butylphenol) | diarylmethane | ||
| oxyclozanide | Oxyclozanide: Anthelmintic used in grazing animals for fasciola and cestode infestations. | ||
| 2,2'-bisphenol f | 2,2'-bisphenol F: contact allergen; structure given in first source | diarylmethane | |
| 8-aminoadenosine | |||
| ver 155008 | VER 155008: structure in first source | purine nucleoside |