ERFAD, ERAD proteiini FOXRED2 (SARS2 COV ORF8 interaktioproteiini)

GeneCArds:
FOXRED2 (22q12.2), FAD-dependent oxidoreductase domain-containing protein 2
https://www.genecards.org/cgi-bin/carddisp.pl?gene=FOXRED2&keywords=FOXRED2

GeneCards Summary for FOXRED2 Gene

FOXRED2 (FAD Dependent Oxidoreductase Domain Containing 2) is a Protein Coding gene. Gene Ontology (GO) annotations related to this gene include oxidoreductase activity. An important paralog of this gene is FMO4.

UniProtKB/Swiss-Prot Summary for FOXRED2 Gene

 Probable flavoprotein which may function in endoplasmic reticulum associated degradation (ERAD). May bind non-native proteins in the endoplasmic reticulum and target them to the ubiquitination machinery for subsequent degradation FXRD2_HUMAN,Q8IWF2

Aliases for FOXRED2 Gene

• FAD Dependent Oxidoreductase Domain Containing 2 ^{2 3 5}
• Endoplasmic Reticulum Flavoprotein Associated With Degradation ^{3 4}
• FAD-Dependent Oxidoreductase Domain-Containing Protein 2 ^{3 4}
• ER Flavoprotein Associated With Degradation ^{2 3}
• ERFAD ^{3 4}

PubMed Gene

FOXRED2

FAD dependent oxidoreductase domain containing 2provided by HGNC

Also known as ERFAD

Expression Ubiquitous expression in brain (RPKM 9.7), ovary (RPKM 6.3) and 24 other tissues See more Orthologs mouse all

1. The flavoprotein FOXRED2 reductively activates nitro-chloromethylbenzindolines and other hypoxia-targeting prodrugs. Hunter FW, et al. Biochem Pharmacol, 2014 May 15. PMID 24632291The nitro-chloromethylbenzindoline prodrug SN29428 has been rationally designed to target tumour hypoxia. SN29428 is metabolised to a DNA minor groove alkylator via oxygen-sensitive reductive activation initiated by unknown one-electron reductases. The present study sought to identify reductases capable of activating SN29428 in tumours. Expression of candidate reductases in cell lines was modulated using forced expression and, for P450 (cytochrome) oxidoreductase (POR), by zinc finger nuclease-mediated gene knockout. Affymetrix microarray mRNA expression of flavoreductases was correlated with SN29428 activation in a panel of 23 cancer cell lines. Reductive activation and cytotoxicity of prodrugs were measured using mass spectrometry and antiproliferative assays, respectively. SN29428 activation under hypoxia was strongly attenuated by the pan-flavoprotein inhibitor diphenyliodonium, but less so by knockout of POR suggesting other flavoreductases contribute. Forced expression of 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR), as well as POR, increased activation of SN29428 in hypoxic HCT 116 cells. SN29428 activation strongly correlated with expression of POR and also FAD-dependent oxidoreductase domain containing 2 (FOXRED2), in cancer cell lines. This association persisted after removing the effect of POR enzyme activity using first-order partial correlation. Forced expression of FOXRED2 increased SN29428 activation and cytotoxicity in hypoxic HEK293 cells and also increased activation of hypoxia-targeted prodrugs PR-104A, tirapazamine and SN30000, and increased cytotoxicity of the clinical-stage prodrug TH-302. Thus this study has identified three flavoreductases capable of enzymatically activating SN29428, one of which (FOXRED2) has not previously been implicated in xenobiotic metabolism. These results will inform future development of biomarkers predictive of SN29428 sensitivity.
2. Identification of the PDI-family member ERp90 as an interaction partner of ERFAD. Riemer J, et al. PLoS One, 2011 Feb 16. PMID 21359175, Free PMC Article  In the endoplasmic reticulum (ER), members of the protein disulfide isomerase (PDI) family perform critical functions during protein maturation. Herein, we identify the previously uncharacterized PDI-family member ERp90. In cultured human cells, we find ERp90 to be a soluble ER-luminal glycoprotein that comprises five potential thioredoxin (Trx)-like domains. Mature ERp90 contains 10 cysteine residues, of which at least some form intramolecular disulfides. While none of the Trx domains contain a canonical Cys-Xaa-Xaa-Cys active-site motif, other conserved cysteines could endow the protein with redox activity. Importantly, we show that ERp90 co-immunoprecipitates with ERFAD, a flavoprotein involved in ER-associated degradation (ERAD), through what is most likely a direct interaction. We propose that the function of ERp90 is related to substrate recruitment or delivery to the ERAD retrotranslocation machinery by ERFAD.
3. Amyloid β-induced FOXRED2 mediates neuronal cell death via inhibition of proteasome activity. Shim S, et al. Cell Mol Life Sci, 2011 Jun. PMID 20972601. Proteasome inhibition has been regarded as one of the mediators of Aβ neurotoxicity. In this study, we found that FOXRED2, a novel endoplasmic reticulum (ER) residential protein, is highly up-regulated by Aβ in rat cortical neurons and SH-SY5Y cells. Over-expression of FOXRED2 inhibits proteasome activity in the microsomal fractions containing ER and interferes with proteasome assembly, as evidenced by gel filtration and native gel electrophoresis analysis. In contrast, reduced expression of FOXRED2 rescues Aβ-induced inhibition of proteasome activity. FOXRED2 is an unstable protein with two degradation boxes and one KEN box, and its N-terminal oxidoreductase domain is required for proteasome inhibition. Ectopic expression of FOXRED2 induces ER stress-mediated cell death via caspase-12, which is inhibited by Salubrinal. Further, down-regulation of FOXRED2 expression attenuates Aβ-induced cell death and the ER stress response. These results suggest that up-regulated FOXRED2 inhibits proteasome activity by interfering with 26S proteasome assembly to contribute to Aβ neurotoxicity via an ER stress response.
4. A luminal flavoprotein in endoplasmic reticulum-associated degradation. Riemer J, et al. Proc Natl Acad Sci U S A, 2009 Sep 1. PMID 19706418, Free PMC Article The quality control system of the endoplasmic reticulum (ER) discriminates between native and nonnative proteins. The latter are degraded by the ER-associated degradation (ERAD) pathway. Whereas many cytosolic and membrane components of this system are known, only few luminal players have been identified. In this study, we characterize ERFAD (ER flavoprotein associated with degradation), an ER luminal flavoprotein that functions in ERAD. Upon knockdown of ERFAD, the degradation of the ERAD model substrate ribophorin 332 is delayed, and the overall level of polyubiquitinated cellular proteins is decreased. We also identify the ERAD components SEL1L, OS-9 and ERdj5, a known reductase of ERAD substrates, as interaction partners of ERFAD. Our data show that ERFAD facilitates the dislocation of certain ERAD substrates to the cytosol, and we discuss the findings in relation to a potential redox function of the protein.
5. Unassembled CD147 is an endogenous endoplasmic reticulum-associated degradation substrate. Tyler RE, et al. Mol Biol Cell, 2012 Dec. PMID 23097496, Free PMC Article
   Abstract

   Degradation of folding- or assembly-defective proteins by the endoplasmic reticulum-associated degradation (ERAD) ubiquitin ligase, Hrd1, is facilitated by a process that involves recognition of demannosylated N-glycans by the lectin OS-9/XTP3-B via the adaptor protein SEL1L. Most of our knowledge of the machinery that commits proteins to this fate in metazoans comes from studies of overexpressed mutant proteins in heterologous cells. In this study, we used mass spectrometry to identify core-glycoslyated CD147 (CD147(CG)) as an endogenous substrate of the ERAD system that accumulates in a complex with OS-9 following SEL1L depletion. CD147 is an obligatory assembly factor for monocarboxylate transporters. The majority of newly synthesized endogenous CD147(CG) was degraded by the proteasome in a Hrd1-dependent manner. CD147(CG) turnover was blocked by kifunensine, and interaction of OS-9 and XTP3-B with CD147(CG) was inhibited by mutations to conserved residues in their lectin domains. These data establish unassembled CD147(CG) as an endogenous, constitutive ERAD substrate of the OS-9/SEL1L/Hrd1 pathway.
   

See all (20) citations in PubMed

GeneRIFs: Gene References Into Functions?

1. Expression of FOXRED2 increases activity of hypoxia-targeted prodrugs.
2. ERFAD facilitates the dislocation of certain endoplasmic reticulum-associated degradation substrates to the cytosol.

Muistiin palautus: CD147  on Basigin!

CD147 as a Target for COVID-19 Treatment: Suggested ...

www.ncbi.nlm.nih.gov › articles › PMC7167302

20 apr. 2020 - CD147, a receptor on host cells, is a novel route for SARS-CoV-2 invasion. Thus, drugs that interfere in the spike protein/CD147 interaction or ...

Identification of endogenous glycan-dependent ERAD substrates

To identify endogenous substrates of the OS-9/SEL1L/Hrd1ligase ERAD pathway, we used LC-MS/MS analysis to identify proteins copurifying with S-protein affinity-purified (SAP) S peptide–tagged OS-9.2 (S-OS-9.2) from digitonin-solubilized HEK293 cells acutely infected with a lentivirus expressing shRNA targeting SEL1L or a control lentivirus (Table 1 and Supplemental Figure S1B). In lysates from control infected cells, S-OS-9.2 interacted robustly (judged by total spectral counts [TSC] and number of unique peptides) with GRP78/BiP, GRP94, and SEL1L—consistent with our previous findings (Christianson et al., 2008)—as well as with known (Mueller et al., 2008; Christianson et al., 2012) membrane and cytosolic interactors of the Hrd1 ligase complex, including Hrd1, Ubc6e, Derlin-2, and VCP/p97. SEL1L knockdown resulted in a complete loss of downstream interactions, confirming the essential role of SEL1L as a link between OS-9 and the membrane-embedded Hrd1 ligase and its associated membrane and cytoplasmic factors. We also observed a concomitant increase in the abundance of Hsp47 and the previously identified OS-9–interacting luminal chaperones, GRP78/BiP and GRP94, after SEL1L knockdown (Christianson et al., 2008).

TABLE 1: LC-MS/MS analysis of S-OS-9.2 affinity-purified complexes from digitonin-solubilized cell lysates.

				Controlc		SEL1L shRNAd
Symbola	Uniprot ID	Protein name	Topologyb	TSCe	Peptides	TSCe	Peptides
OS9	Q13438	OS-9	L	165	58	455	108
HSPA5	P11021	GRP78/BiP	L	179	50	297	63
HSP90B1	P14625	GRP94	L	149	54	200	62
SEL1L	Q9UBV2	SEL1L	TM	21	10
VCP	P55072	p97/VCP	TMf	16	10
SYVN1	Q86TM6	Hrd1	TM	3	1
DERL2	Q9GZP9	Derlin-2	TM	1	1
UBE2J1	Q9Y385	UBC6e	TM	1	1
SERPINH1	P50454	Hsp47	L	7	4	33	14
HYOU1	Q9Y4L1	GRP170	L			13	8
UGCGL2	Q9NYU1	UGGT2	L			10	6
FOXRED2	Q8IWF2	ERFAD	L			3	2
DNAJB11	Q9UBS4	Erdj3	L			2	1
PPIB	P23284	Cyclophilin B	L			2	1
PLOD2	O00469	Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2	L	5	3	24	15
NUP210	Q8TEM1	POM210	TM			12	8
EMMPRIN	P35613	CD147	TM			7	3
GLT25D1	Q8NBJ5	Glycosyltransferase 25 family member 1	L			2	2
CERCAM	Q5T4B2	Glycosyltransferase 25 family member 3	L			2	1

^aGene name.
^bL, lumenal protein; TM, transmembrane domain–containing protein.
^cHEK293 cells infected with an empty lentivirus, not expressing an shRNA.
^dHEK293 cells infected with a lentivirus targeting SEL1L.
^eTSC, total spectral counts.
^fp97/VCP is a cytoplasmic protein that is localized to the ER membrane.