Q8VSC3 · IPA9_SHIFL
- ProteinE3 ubiquitin-protein ligase ipaH9.8
- GeneipaH9.8
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids545 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
Effector E3 ubiquitin ligase that interferes with host's ubiquitination pathway and modulates the acute inflammatory responses, thus facilitating bacterial colonization within the host cell (PubMed:18005683, PubMed:18997778, PubMed:20831869, PubMed:24248594, PubMed:29024643, PubMed:29144452, PubMed:31216343, PubMed:33303953).
Interacts with IKBKG (NEMO) and TNIP1 (ABIN-1), a ubiquitin-binding adapter protein, which results in TNIP1-dependent 'Lys-27'-linked polyubiquitination of IKBKG (PubMed:18005683).
Consequently, polyubiquitinated IKBKG undergoes proteasome-dependent degradation, which perturbs NF-kappa-B activation during bacterial infection (PubMed:18005683, PubMed:20010814).
Mediates polyubiquitination of host U2AF1, leading to its proteasomal degradation (PubMed:15950937).
Catalyzes 'Lys-48'-linked polyubiquitination and subsequent degradation of a subset of host guanylate-binding proteins (GBP1, GBP2, GBP4 and GBP6), thereby suppressing host cell defense (PubMed:29024643, PubMed:29144452, PubMed:31216343, PubMed:33303953, PubMed:37014865).
In contrast, host GBP3 and GBP7 are not ubiquitinated by IpaH9.8 (PubMed:29024643, PubMed:29144452, PubMed:31216343).
Uses UBE2D2 (UBCH5B) as an E2 ubiquitin-conjugating enzyme (PubMed:18005683).
Interacts with IKBKG (NEMO) and TNIP1 (ABIN-1), a ubiquitin-binding adapter protein, which results in TNIP1-dependent 'Lys-27'-linked polyubiquitination of IKBKG (PubMed:18005683).
Consequently, polyubiquitinated IKBKG undergoes proteasome-dependent degradation, which perturbs NF-kappa-B activation during bacterial infection (PubMed:18005683, PubMed:20010814).
Mediates polyubiquitination of host U2AF1, leading to its proteasomal degradation (PubMed:15950937).
Catalyzes 'Lys-48'-linked polyubiquitination and subsequent degradation of a subset of host guanylate-binding proteins (GBP1, GBP2, GBP4 and GBP6), thereby suppressing host cell defense (PubMed:29024643, PubMed:29144452, PubMed:31216343, PubMed:33303953, PubMed:37014865).
In contrast, host GBP3 and GBP7 are not ubiquitinated by IpaH9.8 (PubMed:29024643, PubMed:29144452, PubMed:31216343).
Uses UBE2D2 (UBCH5B) as an E2 ubiquitin-conjugating enzyme (PubMed:18005683).
Catalytic activity
Activity regulation
Exists in an autoinhibited state in the absence of substrate protein, due to interactions of the leucine-rich repeats with NEL domain (PubMed:20831869, PubMed:31216343, PubMed:33303953).
Is activated upon binding to a substrate protein (PubMed:20831869, PubMed:31216343, PubMed:33303953).
Is activated upon binding to a substrate protein (PubMed:20831869, PubMed:31216343, PubMed:33303953).
Pathway
Protein modification; protein ubiquitination.
Features
Showing features for site, active site.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Site | 166 | Sensor for substrate-binding | ||||
Sequence: R | ||||||
Site | 187 | Sensor for substrate-binding | ||||
Sequence: F | ||||||
Active site | 337 | Glycyl thioester intermediate | ||||
Sequence: C |
GO annotations
Aspect | Term | |
---|---|---|
Cellular Component | extracellular region | |
Cellular Component | host cell cytosol | |
Cellular Component | host cell nucleus | |
Molecular Function | identical protein binding | |
Molecular Function | ubiquitin protein ligase activity | |
Molecular Function | ubiquitin-protein transferase activity | |
Biological Process | proteasome-mediated ubiquitin-dependent protein catabolic process | |
Biological Process | protein autoubiquitination | |
Biological Process | protein K27-linked ubiquitination | |
Biological Process | protein K48-linked ubiquitination | |
Biological Process | symbiont-mediated suppression of host defenses | |
Biological Process | symbiont-mediated suppression of host inflammatory response | |
Biological Process | symbiont-mediated suppression of host innate immune response | |
Biological Process | symbiont-mediated suppression of host NF-kappaB cascade | |
Biological Process | ubiquitin-dependent protein catabolic process |
Keywords
- Molecular function
- Biological process
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameE3 ubiquitin-protein ligase ipaH9.8
- EC number
- Alternative names
Gene names
Encoded on
- Plasmid pCP301
- Plasmid pWR100
- Plasmid pWR501
- Plasmid pINV_F6_M1382
- Plasmid pSF5
Organism names
- Organism
- Strains
- Taxonomic lineageBacteria > Pseudomonadota > Gammaproteobacteria > Enterobacterales > Enterobacteriaceae > Shigella
Accessions
- Primary accessionQ8VSC3
- Secondary accessions
Proteomes
Subcellular Location
UniProt Annotation
GO Annotation
Note: Secreted via Mxi-Spa type III secretion system (T3SS), and delivered into the host cytoplasm (PubMed:11115111, PubMed:11418613).
Transported into the host nucleus (PubMed:11418613).
This transport is independent of cytosolic factors, but dependent on temperature and partly on ATP/GTP (PubMed:11418613).
Transported into the host nucleus (PubMed:11418613).
This transport is independent of cytosolic factors, but dependent on temperature and partly on ATP/GTP (PubMed:11418613).
Keywords
- Cellular component
Phenotypes & Variants
Disruption phenotype
In murine lung infection model, mutants cause severe inflammatory responses, with increased pro-inflammatory cytokine production levels. Colonization is greatly reduced.
Features
Showing features for mutagenesis, natural variant.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Mutagenesis | 50 | Abolished ability to bind and ubiquitinate host GBP1; when associated with A-62 and A-83. | ||||
Sequence: L → A | ||||||
Mutagenesis | 62 | Abolished ability to bind and ubiquitinate host GBP1; when associated with A-50 and A-83. | ||||
Sequence: R → A | ||||||
Mutagenesis | 83 | Abolished ability to bind and ubiquitinate host GBP1; when associated with A-50 and A-62. | ||||
Sequence: N → A | ||||||
Mutagenesis | 86-88 | Decreased ability to ubiquitinate host GBP1. | ||||
Sequence: YNQ → ANA | ||||||
Mutagenesis | 126 | Decreased ability to ubiquitinate host GBP1; when associated with A-146. | ||||
Sequence: H → A | ||||||
Mutagenesis | 146 | Decreased ability to ubiquitinate host GBP1; when associated with A-126 or A-190. | ||||
Sequence: Y → A | ||||||
Mutagenesis | 163 | Abolishes proteasomal degradation of host proteins; when associated with A-187 and A-210. | ||||
Sequence: R → A | ||||||
Mutagenesis | 166 | Strongly reduced ability to ubiquitinate host GBP1. | ||||
Sequence: R → A | ||||||
Mutagenesis | 187 | Abolishes proteasomal degradation of host proteins; when associated with A-163 and A-210. | ||||
Sequence: F → A | ||||||
Mutagenesis | 190 | Decreased ability to ubiquitinate host GBP1; when associated with A-146. | ||||
Sequence: R → A | ||||||
Mutagenesis | 196 | Does not affect autoinhibition in absence of substrate. | ||||
Sequence: I → A | ||||||
Mutagenesis | 196 | Reduced autoinhibition in absence of substrate. | ||||
Sequence: I → D | ||||||
Mutagenesis | 198 | Does not affect autoinhibition in absence of substrate. | ||||
Sequence: E → A | ||||||
Mutagenesis | 210 | Abolishes proteasomal degradation of host proteins; when associated with A-163 and A-187. | ||||
Sequence: H → A | ||||||
Mutagenesis | 211 | Slightly reduced autoinhibition in absence of substrate. | ||||
Sequence: I → D | ||||||
Mutagenesis | 216 | Slightly reduced autoinhibition in absence of substrate. | ||||
Sequence: L → D | ||||||
Mutagenesis | 219 | Does not affect autoinhibition in absence of substrate. | ||||
Sequence: H → A | ||||||
Natural variant | 222 | in plasmid pWR100, plasmid pWR501, plasmid pSF5 and plasmid pINV_F6_M1382 | ||||
Sequence: P → Q | ||||||
Mutagenesis | 337 | Abolishes E3 ubiquitin ligase activity and proteasomal degradation of host proteins. | ||||
Sequence: C → A | ||||||
Mutagenesis | 338 | Does not affect E3 ubiquitin ligase activity. | ||||
Sequence: E → A | ||||||
Mutagenesis | 339 | Abolishes E3 ubiquitin ligase activity. | ||||
Sequence: D → A | ||||||
Mutagenesis | 340 | Reduced E3 ubiquitin ligase activity. | ||||
Sequence: R → A | ||||||
Mutagenesis | 387 | Does not affect E3 ubiquitin ligase activity. | ||||
Sequence: R → A | ||||||
Mutagenesis | 395 | Does not affect autoinhibition in absence of substrate. | ||||
Sequence: F → A | ||||||
Mutagenesis | 395 | Reduced autoinhibition in absence of substrate. | ||||
Sequence: F → R | ||||||
Mutagenesis | 397 | Abolishes E3 ubiquitin ligase activity. | ||||
Sequence: D → A | ||||||
Natural variant | 474 | in plasmid pINV_F6_M1382 | ||||
Sequence: Q → L | ||||||
Natural variant | 536 | in plasmid pWR100 and plasmid pWR501 | ||||
Sequence: P → F | ||||||
Natural variant | 536 | in plasmid pSF5 | ||||
Sequence: P → S |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 4 variants from UniProt as well as other sources including ClinVar and dbSNP.
PTM/Processing
Features
Showing features for chain.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Chain | PRO_0000395755 | 1-545 | E3 ubiquitin-protein ligase ipaH9.8 | |||
Sequence: MLPINNNFSLPQNSFYNTISGTYADYFSAWDKWEKQALPGEERDEAVSRLKECLINNSDELRLDRLNLSSLPDNLPAQITLLNVSYNQLTNLPELPVTLKKLYSASNKLSELPVLPPALESLQVQHNELENLPALPDSLLTMNISYNEIVSLPSLPQALKNLRATRNFLTELPAFSEGNNPVVREYFFDRNQISHIPESILNLRNECSIHISDNPLSSHALPALQRLTSSPDYHGPRIYFSMSDGQQNTLHRPLADAVTAWFPENKQSDVSQIWHAFEHEEHANTFSAFLDRLSDTVSARNTSGFREQVAAWLEKLSASAELRQQSFAVAADATESCEDRVALTWNNLRKTLLVHQASEGLFDNDTGALLSLGREMFRLEILEDIARDKVRTLHFVDEIEVYLAFQTMLAEKLQLSTAVKEMRFYGVSGVTANDLRTAEAMVRSREENEFTDWFSLWGPWHAVLKRTEADRWAQAEEQKYEMLENEYPQRVADRLKASGLSGDADAEREAGAQVMRETEQQIYRQLTDEVLALRLPENGSQLHHS |
Post-translational modification
Autoubiquitinated (in vitro) (PubMed:20831869).
Ubiquitinated in the presence of host E1 ubiquitin-activating enzyme, E2 ubiquitin-conjugating enzyme and ubiquitin (PubMed:20831869).
Ubiquitinated in the presence of host E1 ubiquitin-activating enzyme, E2 ubiquitin-conjugating enzyme and ubiquitin (PubMed:20831869).
Keywords
- PTM
Proteomic databases
Expression
Induction
Induced upon entry into host epithelial cells.
Interaction
Subunit
Interacts also with human and mouse U2AF1 (U2AF35).
Binary interactions
Type | Entry 1 | Entry 2 | Number of experiments | Intact | |
---|---|---|---|---|---|
XENO | Q8VSC3 | IKBKG Q9Y6K9 | 8 | EBI-6125799, EBI-81279 | |
BINARY | Q8VSC3 | ipaH9.8 Q8VSC3 | 3 | EBI-6125799, EBI-6125799 | |
XENO | Q8VSC3 | TNIP1 Q15025 | 4 | EBI-6125799, EBI-357849 |
Protein-protein interaction databases
Structure
Family & Domains
Features
Showing features for region, repeat, domain.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Region | 1-242 | Interaction with target proteins | ||||
Sequence: MLPINNNFSLPQNSFYNTISGTYADYFSAWDKWEKQALPGEERDEAVSRLKECLINNSDELRLDRLNLSSLPDNLPAQITLLNVSYNQLTNLPELPVTLKKLYSASNKLSELPVLPPALESLQVQHNELENLPALPDSLLTMNISYNEIVSLPSLPQALKNLRATRNFLTELPAFSEGNNPVVREYFFDRNQISHIPESILNLRNECSIHISDNPLSSHALPALQRLTSSPDYHGPRIYFSM | ||||||
Repeat | 57-77 | LRR 1 | ||||
Sequence: NSDELRLDRLNLSSLPDNLPA | ||||||
Repeat | 78-99 | LRR 2 | ||||
Sequence: QITLLNVSYNQLTNLPELPVTL | ||||||
Repeat | 100-117 | LRR 3 | ||||
Sequence: KKLYSASNKLSELPVLPP | ||||||
Repeat | 118-139 | LRR 4 | ||||
Sequence: ALESLQVQHNELENLPALPDSL | ||||||
Repeat | 140-157 | LRR 5 | ||||
Sequence: LTMNISYNEIVSLPSLPQ | ||||||
Repeat | 158-179 | LRR 6 | ||||
Sequence: ALKNLRATRNFLTELPAFSEGN | ||||||
Repeat | 182-203 | LRR 7 | ||||
Sequence: VVREYFFDRNQISHIPESILNL | ||||||
Repeat | 205-228 | LRR 8 | ||||
Sequence: NECSIHISDNPLSSHALPALQRLT | ||||||
Region | 243-250 | Linker | ||||
Sequence: SDGQQNTL | ||||||
Region | 251-545 | E3 ubiquitin-protein ligase catalytic domain | ||||
Sequence: HRPLADAVTAWFPENKQSDVSQIWHAFEHEEHANTFSAFLDRLSDTVSARNTSGFREQVAAWLEKLSASAELRQQSFAVAADATESCEDRVALTWNNLRKTLLVHQASEGLFDNDTGALLSLGREMFRLEILEDIARDKVRTLHFVDEIEVYLAFQTMLAEKLQLSTAVKEMRFYGVSGVTANDLRTAEAMVRSREENEFTDWFSLWGPWHAVLKRTEADRWAQAEEQKYEMLENEYPQRVADRLKASGLSGDADAEREAGAQVMRETEQQIYRQLTDEVLALRLPENGSQLHHS | ||||||
Domain | 261-471 | NEL | ||||
Sequence: WFPENKQSDVSQIWHAFEHEEHANTFSAFLDRLSDTVSARNTSGFREQVAAWLEKLSASAELRQQSFAVAADATESCEDRVALTWNNLRKTLLVHQASEGLFDNDTGALLSLGREMFRLEILEDIARDKVRTLHFVDEIEVYLAFQTMLAEKLQLSTAVKEMRFYGVSGVTANDLRTAEAMVRSREENEFTDWFSLWGPWHAVLKRTEADR |
Domain
The LRR (leucine-rich repeat) repeats are involved in substrate recognition with target proteins.
Sequence similarities
Belongs to the LRR-containing bacterial E3 ligase family.
Keywords
- Domain
Phylogenomic databases
Family and domain databases
Sequence
- Sequence statusComplete
- Length545
- Mass (Da)61,979
- Last updated2005-01-04 v2
- Checksum5E70042D797B5099
Sequence caution
Features
Showing features for sequence conflict.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Sequence conflict | 7 | in Ref. 2; AA sequence | ||||
Sequence: Missing |
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AF047365 EMBL· GenBank· DDBJ | AAC23714.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AL391753 EMBL· GenBank· DDBJ | CAC05853.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AF348706 EMBL· GenBank· DDBJ | AAK18544.1 EMBL· GenBank· DDBJ | Genomic DNA | Different initiation | |
AY206445 EMBL· GenBank· DDBJ | AAP79029.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AY879342 EMBL· GenBank· DDBJ | AAW64849.1 EMBL· GenBank· DDBJ | Genomic DNA | Different initiation | |
AF386526 EMBL· GenBank· DDBJ | AAL72345.2 EMBL· GenBank· DDBJ | Genomic DNA |