SlrP (Salmonella leucine-rich repeat protein) is a type III secretion system (T3SS) effector protein in Salmonella enterica serovar Typhimurium. It belongs to the LRR-containing bacterial E3 ubiquitin ligase family (IpaH-like) and contains an N-terminal leucine-rich repeat domain that mediates target recognition and a C-terminal NEL (novel E3 ligase) domain with E3 ubiquitin ligase catalytic activity (Cys-546 is the catalytic residue). SlrP is secreted via both SPI-1 and SPI-2 T3SS into host cells, where it ubiquitinates host thioredoxin (TXN) in the cytosol, leading to decreased TXN activity and increased host cell death (PMID:19690162). It also targets the ER lumenal chaperone ERdj3 (DNAJB11), interfering with ERdj3's binding to denatured substrates (PMID:20335166). SlrP is a virulence factor, not a chaperone.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004842 ubiquitin-protein transferase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Combined IEA annotation for ubiquitin-protein transferase activity based on ARBA and InterPro (NEL domain). SlrP has E3 ubiquitin ligase activity demonstrated experimentally (PMID:19690162). Reason: Correct. SlrP is an E3 ubiquitin ligase demonstrated to ubiquitinate both ubiquitin and host thioredoxin (PMID:19690162). Consistent with IDA evidence. |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | MARK AS OVER ANNOTATED | Summary: IEA annotation for extracellular region from UniProt subcellular location mapping. SlrP is a T3SS effector translocated into host cells, but the secretion route alone does not establish extracellular-region localization as a biologically meaningful site of function. Reason: UniProt "Secreted" keyword mapping is imprecise for a T3SS effector that is directly delivered into host cells. The supported functional locations are host cell cytoplasm and host cell endoplasmic reticulum, where SlrP targets thioredoxin and ERdj3. |
| GO:0016567 protein ubiquitination | IEA GO_REF:0000120 | ACCEPT | Summary: Combined IEA annotation for protein ubiquitination based on ARBA and InterPro (NEL domain). SlrP ubiquitinates host thioredoxin (PMID:19690162). Reason: Correct. SlrP mediates ubiquitination of host thioredoxin and ubiquitin itself in vitro (PMID:19690162). Consistent with IDA evidence. |
| GO:0016740 transferase activity | IEA GO_REF:0000043 | ACCEPT | Summary: IEA annotation for transferase activity from UniProt keyword mapping. This is a broad parent of ubiquitin-protein transferase activity. Reason: Correct but very broad. The more specific terms GO:0004842 and GO:0061630 are also annotated. Acceptable as a broad IEA. |
| GO:0030430 host cell cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: IEA annotation for host cell cytoplasm from UniProt subcellular location mapping. SlrP is translocated into the host cell cytoplasm via T3SS (PMID:20335166). Reason: Correct. SlrP is delivered into the host cell cytoplasm where it targets thioredoxin for ubiquitination. Consistent with IDA evidence (PMID:20335166). |
| GO:0061630 ubiquitin protein ligase activity | IEA GO_REF:0000003 | ACCEPT | Summary: IEA annotation for ubiquitin protein ligase activity from EC mapping (EC 2.3.2.27). SlrP is annotated as E3 ubiquitin-protein ligase in UniProt with EC 2.3.2.27. Reason: Correct and more specific than GO:0004842 for describing the E3 ligase function. SlrP functions as an E3 ubiquitin ligase (PMID:19690162). |
| GO:0005515 protein binding | IPI PMID:20335166 The Salmonella type III secretion effector, salmonella leuci... | MARK AS OVER ANNOTATED | Summary: IPI annotation for protein binding showing interaction with ERdj3 (DNAJB11, Q9UBS4). SlrP binds ERdj3 via its leucine-rich repeat domain and interferes with ERdj3's chaperone function (PMID:20335166). Reason: Protein binding (GO:0005515) is uninformative. The interaction with ERdj3 is real but the generic term does not convey the functional significance. The interaction is part of SlrP's virulence mechanism targeting the host ER chaperone ERdj3 for functional disruption. |
| GO:0044165 host cell endoplasmic reticulum | IDA PMID:20335166 The Salmonella type III secretion effector, salmonella leuci... | ACCEPT | Summary: IDA annotation for host cell ER localization. Confocal microscopy and subcellular fractionation showed that SlrP is partially located in the ER of transfected HeLa cells (PMID:20335166). Reason: Direct experimental evidence from confocal microscopy and subcellular fractionation (PMID:20335166). SlrP localizes to the host ER where it targets ERdj3. Supporting Evidence: PMID:20335166 Confocal microscopy and subcellular fractionation demonstrated that, in transfected HeLa cells, SlrP was partially located in the endoplasmic reticulum. |
| GO:0051082 unfolded protein binding | IPI PMID:20335166 The Salmonella type III secretion effector, salmonella leuci... | REMOVE | Summary: IPI annotation for unfolded protein binding based on interaction with ERdj3 (Q9UBS4). However, SlrP does not bind unfolded proteins itself. Rather, SlrP binds the chaperone ERdj3 and interferes with ERdj3's ability to bind denatured substrates (PMID:20335166). The "unfolded protein binding" annotation appears to be a misannotation -- SlrP disrupts chaperone function, it does not itself bind unfolded proteins in a chaperone-like manner. Reason: This annotation is incorrect. SlrP does not bind unfolded proteins. The paper (PMID:20335166) shows that SlrP binds ERdj3 (a chaperone) and interferes with ERdj3's binding to a denatured substrate. The IPI with/from column shows Q9UBS4 (ERdj3/DNAJB11), which is a folded chaperone protein, not an unfolded protein. The annotation confuses SlrP's interaction with a chaperone with binding to unfolded proteins. SlrP is a virulence factor/E3 ubiquitin ligase that targets specific host proteins (thioredoxin, ERdj3) for functional disruption, not a protein that binds unfolded substrates. Supporting Evidence: PMID:20335166 The presence of SlrP interfered with the binding of ERdj3 to a denatured substrate. |
| GO:0030430 host cell cytoplasm | IDA PMID:20335166 The Salmonella type III secretion effector, salmonella leuci... | ACCEPT | Summary: IDA annotation for host cell cytoplasm from Bernal-Bayard et al. (2010). Consistent with IEA annotation and the known T3SS-mediated delivery of SlrP into host cells. Reason: Correct. Direct experimental evidence for host cell cytoplasm localization. SlrP targets thioredoxin in the cytosol and ERdj3 in the ER (PMID:20335166). |
| GO:0032091 negative regulation of protein binding | IDA PMID:20335166 The Salmonella type III secretion effector, salmonella leuci... | ACCEPT | Summary: IDA annotation for negative regulation of protein binding. SlrP interferes with ERdj3's ability to bind denatured substrates (PMID:20335166). This captures SlrP's virulence mechanism of disrupting host chaperone function. Reason: This accurately describes the functional consequence of SlrP-ERdj3 interaction: SlrP negatively regulates ERdj3's protein binding (chaperone) activity. This is a documented virulence mechanism (PMID:20335166). Supporting Evidence: PMID:20335166 The presence of SlrP interfered with the binding of ERdj3 to a denatured substrate. |
| GO:0004842 ubiquitin-protein transferase activity | IDA PMID:19690162 Salmonella type III secretion effector SlrP is an E3 ubiquit... | ACCEPT | Summary: IDA annotation for ubiquitin-protein transferase activity from Bernal-Bayard and Ramos-Morales (2009). SlrP mediates ubiquitination of ubiquitin and host thioredoxin in vitro. Cys-546 to Ala mutation abolishes this activity (PMID:19690162). Reason: Core molecular function of SlrP. Directly demonstrated by in vitro ubiquitination assays with Cys-546 mutant as negative control (PMID:19690162). Supporting Evidence: PMID:19690162 In vitro, SlrP was able to mediate ubiquitination of ubiquitin and thioredoxin. |
| GO:0005515 protein binding | IPI PMID:19690162 Salmonella type III secretion effector SlrP is an E3 ubiquit... | MARK AS OVER ANNOTATED | Summary: IPI annotation for protein binding showing interaction with host thioredoxin (TXN, P10599). SlrP binds thioredoxin as its ubiquitination substrate (PMID:19690162). Reason: Protein binding (GO:0005515) is uninformative. The interaction with thioredoxin is real but the generic term does not capture the functional significance -- SlrP binds TXN as an E3 ubiquitin ligase substrate. The ubiquitin ligase activity annotations already capture this function more informatively. |
| GO:0016567 protein ubiquitination | IDA PMID:19690162 Salmonella type III secretion effector SlrP is an E3 ubiquit... | ACCEPT | Summary: IDA annotation for protein ubiquitination from Bernal-Bayard and Ramos-Morales (2009). SlrP ubiquitinates host thioredoxin (PMID:19690162). Reason: Core biological process of SlrP. Directly demonstrated by ubiquitination assays (PMID:19690162). Consistent with IEA annotation. Supporting Evidence: PMID:19690162 In vitro, SlrP was able to mediate ubiquitination of ubiquitin and thioredoxin. |
| GO:0030254 protein secretion by the type III secretion system | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation for T3SS-mediated secretion based on manual transfer from ortholog. SlrP is translocated via both SPI-1 and SPI-2 T3SS into host cells. Reason: Correct. SlrP is a well-characterized T3SS effector secreted via both SPI-1 and SPI-2 systems. This is fundamental to its delivery mechanism. |
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