1. Gene Aliases

Sulfiredoxin 1, SRX1, C20orf139, Npn3, Sulfiredoxin-1, DJ850E9.2, SRX, Chromosome 20 Open Reading Frame 139, EC 1.8.98.2

[https://www.genecards.org/cgi-bin/carddisp.pl?gene=SRXN1&keywords=SRXN1]

2. Association with Toxicity and/or Disease at a Transcriptional Level

3. Summary of Protein Family and Structure

4. Proteins Known to Interact with Gene Product

Interactions with experimental support

Interactions with text mining support

5. Links to Gene Databases

6. GO Terms, MSigDB Signatures, Pathways Containing Gene with Descriptions of Gene Sets

Pathways:

NFE2L2 regulating anti-oxidant/detoxification enzymes: Subpathway representing cytoprotective genes regulated by NFE2L2 (NRF2). NFE2L2 is well-studied for its role in oxidative stress where it gets activated by ROS and then induces a plethora of gene expression regulation the oxidative damage. It induces genes/enzymes that regulate the phase 2 detoxification system (eg. GSTs and Glutathione system), ROS scavenging (SODs,PRDX1 ) and cytoprotection (HO1) by regulating inflammation and tissue damage (Tonelli et al, 2018; Shaw et al, 2020) [https://reactome.org/PathwayBrowser/#/R-HSA-9818027].

KEAP1-NFE2L2 pathway: The KEAP1:NFE2L2 (KEAP1-NRF2, Kelch-like ECH-associated protein 1-Nuclear Factor (erythroid-derived 2)-like 2) regulatory pathway plays a central role in protecting cells against multiple homeostatic responses including adaptation to oxidative, inflammatory, metabolic, proteotoxic and xenobiotic stresses. The NFE2L2 transcriptome has been implicated in protection against many chronic diseases including cardiovascular, metabolic, neurodgenerative and respiratory diseases (reviewed in Cuadrado et al, 2018; Baird and Yamamoto, 2020). In cancer, NFE2L2 plays a critical role in the metabolic reprogramming, directing metabolic intermediates into the Warburg and pentose phosphate pathways to support proliferative growth and redox homeostasis (reviewed in He et al, 2020; Ge et al, 2020; Hayes et al, 2020; Kitamura and Hotomashi, 2018).

KEAP1 is a redox sensor that together with CUL3/RBX1 forms part of an E3 ubiquitin ligase, which tightly regulates the activity of the transcription factor NFE2L2 by targeting it for ubiquitination and proteasome-dependent degradation. Oxidative modifications or electrophile adduct formation with redox-sensitive cysteines within KEAP1 renders this protein unable to target bound NFE2L2 for ubiquitination and allows newly translated NFE2L2 to accumulate within the cell and translocate to the nucleus where it can promote its transcriptional program (reviewed in Cuadrado et al, 2019; Baird and Yamamoto, 2020) [https://reactome.org/PathwayBrowser/#/R-HSA-9755511].

GO terms:

cellular oxidant detoxification [Any process carried out at the cellular level that reduces or removes the toxicity superoxide radicals or hydrogen peroxide. GO:0098869]

cellular response to oxidative stress [Any process that results in a change in state or activity of a cell (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of oxidative stress, a state often resulting from exposure to high levels of reactive oxygen species, e.g. superoxide anions, hydrogen peroxide (H2O2), and hydroxyl radicals. GO:0034599]

response to oxidative stress [Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of oxidative stress, a state often resulting from exposure to high levels of reactive oxygen species, e.g. superoxide anions, hydrogen peroxide (H2O2), and hydroxyl radicals. GO:0006979]

MSigDB Signatures:

ACEVEDO_LIVER_TUMOR_VS_NORMAL_ADJACENT_TISSUE_UP: Genes up-regulated in liver tumor compared to the normal adjacent tissue. [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/ACEVEDO_LIVER_TUMOR_VS_NORMAL_ADJACENT_TISSUE_UP.html]

ACEVEDO_LIVER_CANCER_UP: Genes up-regulated in hepatocellular carcinoma (HCC) compared to normal liver samples. [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/ACEVEDO_LIVER_CANCER_UP.html]

PATIL_LIVER_CANCER: Genes up-regulated in hepatocellular carcinoma (HCC) compared to normal liver samples. [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/PATIL_LIVER_CANCER.html]

WP_NRF2_PATHWAY: NRF2 pathway [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/WP_NRF2_PATHWAY.html]

WP_NUCLEAR_RECEPTORS_META_PATHWAY: Nuclear receptors meta pathway [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/WP_NUCLEAR_RECEPTORS_META_PATHWAY.html]

REACTOME_NFE2L2_REGULATING_ANTI_OXIDANT_DETOXIFICATION_ENZYMES: NFE2L2 regulating anti-oxidant/detoxification enzymes [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_NFE2L2_REGULATING_ANTI_OXIDANT_DETOXIFICATION_ENZYMES.html]

REACTOME_KEAP1_NFE2L2_PATHWAY: KEAP1-NFE2L2 pathway [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_KEAP1_NFE2L2_PATHWAY.html]

GARGALOVIC_RESPONSE_TO_OXIDIZED_PHOSPHOLIPIDS_BLUE_UP: Genes from the blue module which are up-regulated in HAEC cells (primary aortic endothelium) after exposure to the oxidized 1-palmitoyl-2-arachidonyl-sn-3-glycerophosphorylcholine (oxPAPC). [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/GARGALOVIC_RESPONSE_TO_OXIDIZED_PHOSPHOLIPIDS_BLUE_UP.html]

REACTOME_CELLULAR_RESPONSE_TO_CHEMICAL_STRESS: Cellular response to chemical stress [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_CELLULAR_RESPONSE_TO_CHEMICAL_STRESS.html]

REACTOME_NUCLEAR_EVENTS_MEDIATED_BY_NFE2L2: Nuclear events mediated by NFE2L2 [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_NUCLEAR_EVENTS_MEDIATED_BY_NFE2L2.html]

REACTOME_CELLULAR_RESPONSES_TO_STIMULI: Cellular responses to stimuli [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_CELLULAR_RESPONSES_TO_STIMULI.html]

IBRAHIM_NRF2_UP: Genes up-regulated in HEK293T cells overexpressing FLAG-NRF2 [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/IBRAHIM_NRF2_UP.html]

JINESH_BLEBBISHIELD_TRANSFORMED_STEM_CELL_SPHERES_UP: Genes up-regulated in transformed spheres compared to blebbishields from RT4 cells [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/JINESH_BLEBBISHIELD_TRANSFORMED_STEM_CELL_SPHERES_UP.html]

NAKAMURA_TUMOR_ZONE_PERIPHERAL_VS_CENTRAL_UP: Up-regulated genes in peripheral zone of human pancreatic cancer growing in the pancreas of nude mice compared to that of the tumor from the central zone. [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/NAKAMURA_TUMOR_ZONE_PERIPHERAL_VS_CENTRAL_UP.html]

7. Gene Descriptions

NCBI Gene Summary: Enables oxidoreductase activity, acting on a sulfur group of donors. Involved in response to oxidative stress. Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

GeneCards Summary: SRXN1 (Sulfiredoxin 1) is a Protein Coding gene. Among its related pathways are Nuclear events mediated by NFE2L2 and Cellular responses to stimuli. Gene Ontology (GO) annotations related to this gene include oxidoreductase activity, acting on a sulfur group of donors and sulfiredoxin activity.

UniProtKB/Swiss-Prot Summary: Contributes to oxidative stress resistance by reducing cysteine-sulfinic acid formed under exposure to oxidants in the peroxiredoxins PRDX1, PRDX2, PRDX3 and PRDX4 [PMID: 15448164, PMID: 15590625]. Does not act on PRDX5 or PRDX6 [PMID: 15448164, PMID: 15590625]. May catalyze the reduction in a multi-step process by acting both as a specific phosphotransferase and a thioltransferase [PMID: 15448164, PMID: 15590625].

8. Cellular Location of Gene Product

Predicted location: Intracellular [https://www.proteinatlas.org/ENSG00000271303/subcellular]

9. Mechanistic Information

Summary

Srxn1 encodes the enzyme sulfiredoxin 1 which specifically targets hyperoxidized 2-cys peroxiredoxins including PRDX1, PRDX2, PRDX3, and PRDX4, reducing the sulfinic form (-SO2H) of the peroxiredoxin active site cysteine back to the sulfenic form (-SOH). This regeneration is vital as peroxiredoxins are responsible for breaking down hydrogen peroxide, a reactive oxygen species, thereby mitigating oxidative stress within hepatocytes [CS: 9]. In the context of pervasive exogenous and endogenous oxidative insults that the liver must process, such as xenobiotics and metabolic byproducts, maintaining functional peroxiredoxins is essential for cell survival and detoxification efficiency [CS: 8].

In diseases like hepatocellular carcinoma (HCC) and during certain toxic exposures like glutathione depletion, the liver experiences heightened levels of oxidative stress, prompting an increase in Srxn1 gene expression [CS: 7]. The elevated Srxn1 gene expression allows for greater production of sulfiredoxin-1, enhancing the cellular capacity to repair oxidatively modified peroxiredoxins and maintain the redox balance within hepatocytes [CS: 8]. This adaptive response to increased oxidative stress aims to preserve liver function and survivability under adverse conditions [CS: 8]. Additionally, SRXN1 upregulation triggers downstream antioxidant defense pathways regulated by the transcription factor Nrf2 [CS: 9]. The activation of the Nrf2 pathway boosts the production of additional antioxidant enzymes like glutathione-S transferase and hemeoxygenase-1, further strengthening the cell's protective mechanisms against oxidative stress [CS: 9].

10. Upstream Regulators

11. Tissues/Cell Type Where Genes are Overexpressed

Tissue type enchanced: low tissue specificity [https://www.proteinatlas.org/ENSG00000271303/tissue]

Cell type enchanced: excitatory neurons, inhibitory neurons, mesothelial cells, pancreatic endocrine cells, squamous epithelial cells (cell type enhanced) [https://www.proteinatlas.org/ENSG00000271303/single+cell+type]

12. Role of Gene in Other Tissues

13. Chemicals Known to Elicit Transcriptional Response of Biomarker in Tissue of Interest

Compounds that increase expression of the gene:

Compounds that decrease expression of the gene:

14. DisGeNet Biomarker Associations to Disease in Organ of Interest