Gene Ontology annotation through association of InterPro records with GO terms
Gene Ontology annotation based on Enzyme Commission mapping
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
Electronic Gene Ontology annotations created by ARBA machine learning models
Shigella protein IpaH(9.8) is secreted from bacteria within mammalian cells and transported to the nucleus.
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IpaH proteins are secreted by Shigella into the extracellular medium via the type III secretion system, later in the secretion hierarchy than the IpaBCD translocators.
"Upon incubation in a medium containing Congo red, the bacteria secrete IpaH into the medium, but secretion of IpaH occurs later than that of IpaBCD."
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The nuclear import described in this paper is a property of the paralog IpaH9.8 and is not reported for IpaH4.5.
"Immunofluorescence microscopy indicated that IpaH(9.8) is secreted from intracellular bacteria and transported into the nucleus."
Shigella flexneri T3SS effector IpaH4.5 modulates the host inflammatory response via interaction with NF-κB p65 protein.
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IpaH4.5 binds the p65 subunit of NF-kappaB through its N-terminal region and ubiquitinates it, and it suppresses NF-kappaB-dependent transcription.
"In vitro, IpaH4.5 displayed ubiquitin ligase activity towards ubiquitin and p65."
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Deletion of ipaH4.5 increases host inflammation and reduces bacterial colonization in a murine lung infection model and the Sereny test.
"the Shigella ΔipaH4.5 mutant strain caused more severe inflammatory responses and significantly induced higher pro-inflammatory cytokine levels (MIP-2 and TNF-α)"
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The suppression this paper measures is of NF-kappaB-driven transcription; it reports no assay of host mRNA translation, which is why the CACAO GO:0039604 annotation keyed to it names the wrong molecular step.
"the transcriptional activity of NF-κB was shown to be inhibited by IpaH4.5 utilizing a dual-luciferase reporter gene detection system containing NF-κB promoter response elements"
Bacterial E3 Ubiquitin Ligase IpaH4.5 of Shigella flexneri Targets TBK1 To Dampen the Host Antibacterial Response.
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IpaH4.5 binds TBK1 and attaches K48-linked polyubiquitin chains to it, targeting the kinase for proteasomal degradation.
"IpaH4.5 interacts with TBK1 and promotes its K48-linked polyubiquitylation."
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Loss of TBK1 prevents IRF3 phosphorylation, nuclear translocation and activation, dampening the host antibacterial response.
"polyubiquitylated TBK1 undergoes proteasome-dependent degradation, which perturbs the phosphorylation, nuclear translocation, and activation of IRF3"
Shigella effector IpaH4.5 targets 19S regulatory particle subunit RPN13 in the 26S proteasome to dampen cytotoxic T lymphocyte activation.
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IpaH4.5 ubiquitinates the 19S regulatory particle subunit RPN13 and drives its degradation through the ubiquitin-proteasome system, disorganizing the 26S proteasome and reducing MHC class I antigen cross-presentation to CD8+ T cells.
"targets the proteasome regulatory particle non-ATPase 13 (RPN13) and induces its degradation via the ubiquitin-proteasome system (UPS)"
The Shigella Type III Secretion Effector IpaH4.5 Targets NLRP3 to Activate Inflammasome Signaling.
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IpaH4.5 catalyses mainly K63-linked ubiquitination of NLRP3, and the catalytically dead C379A variant does not, identifying Cys379 as the active-site cysteine of the NEL domain in this protein.
"mutation of the IpaH4.5 E3 ligase motif (C379A mutant) did not upregulate NLRP3 ubiquitination to the same intensity as wildtype IpaH4.5 (Figure 2A)"
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IpaH4.5 raises NLRP3 protein without changing NLRP3 mRNA, so it stabilizes the protein post-transcriptionally, and it does not affect NLRC4.
"Quantitative RT-PCR showed that NLRP3 mRNA levels were not affected by IpaH4.5 overexpression (Figure 3D), suggesting that IpaH4.5 stabilized NLRP3 protein by posttranscriptional modification."
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IpaH4.5 increases caspase-1 activation, IL-1 beta production and pyroptosis in Shigella-infected macrophages, and this requires its E3 ligase activity.
"Mutation of the IpaH4.5 E3 ligase motif not only abolishes NLRP3 inflammasome signaling but also dramatically reduces the ability of Shigella to induce cell pyroptosis."
Shigella escapes lysosomal degradation through inactivation of Rab31 by IpaH4.5.
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This paper reports that IpaH4.5 carries TBC-like dual-finger motifs and acts as a Rab31 GTPase-activating protein, disrupting CD-MPR trafficking from Golgi to endosome and attenuating lysosomal function. The claim is recorded here but is not annotated, because a GAP activity would be a second catalytic function in a protein whose only recognized catalytic module is the NEL domain, and no TBC-like motif is annotated in P18009.
"IpaH4.5 harbours TBC-like dual-finger motifs and exhibits potent RabGAP activities towards Rab31."
Sequence variation in two ipaH genes of Shigella flexneri 5 and homology to the LRG-like family of proteins.
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IpaH4.5 and IpaH7.8 are related proteins that differ in their N-terminal region (the first 197 residues of IpaH7.8 are replaced by a distinct 251 residues in IpaH4.5) while sharing the rest, and the IpaH4.5 N-terminus carries a leucine-rich internal repeat structure.
"The first 197 amino acids in IpaH7.8 were replaced in IpaH4.5 by a unique set of 251 amino acids, generating two related proteins with variable and conserved sequences."
UniProtKB entry P18009 (IPA4_SHIFL), Probable E3 ubiquitin-protein ligase ipaH4.5
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The NEL catalytic domain spans residues 295-574 and the active site is residue 379, annotated as forming a glycyl thioester intermediate; residue 379 of the P18009 sequence is a cysteine, which makes the mechanism HECT-like rather than RING-type.
"/note="Glycyl thioester intermediate""
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The N-terminal leucine-rich repeat solenoid (LRRs 1-10, residues 63-270) is the substrate-recognition module.
"The LRR (leucine-rich repeat) domain forms a slightly curved solenoid and may mediate interaction with target proteins."