InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: ITCH

Summary

InnateDB Protein

IDBP-68149.7

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

ITCH

Protein Name

itchy E3 ubiquitin protein ligase homolog (mouse)

Synonyms

Species

Homo sapiens

Ensembl Protein

ENSP00000363998

InnateDB Gene

IDBG-68143 (ITCH)

Protein Structure

UniProt Annotation

Function

Acts as an E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. It catalyzes 'Lys-29'-, 'Lys-48'- and 'Lys-63'-linked ubiquitin conjugation. It is involved in the control of inflammatory signaling pathways. Is an essential component of a ubiquitin-editing protein complex, comprising also TNFAIP3, TAX1BP1 and RNF11, that ensures the transient nature of inflammatory signaling pathways. Promotes the association of the complex after TNF stimulation. Once the complex is formed, TNFAIP3 deubiquitinates 'Lys-63' polyubiquitin chains on RIPK1 and catalyzes the formation of 'Lys-48'-polyubiquitin chains. This leads to RIPK1 proteasomal degradation and consequently termination of the TNF- or LPS-mediated activation of NFKB1. Ubiquitinates RIPK2 by 'Lys-63'-linked conjugation and influences NOD2-dependent signal transduction pathways. Regulates the transcriptional activity of several transcription factors, and probably plays an important role in the regulation of immune response. Ubiquitinates NFE2 by 'Lys-63' linkages and is implicated in the control of the development of hematopoietic lineages. Critical regulator of T-helper (TH2) cytokine development through its ability to induce JUNB ubiquitination and degradation (By similarity). Ubiquitinates SNX9. Ubiquitinates CXCR4 and HGS/HRS and regulates sorting of CXCR4 to the degradative pathway. It is involved in the negative regulation of MAVS-dependent cellular antiviral responses. Ubiquitinates MAVS through 'Lys-48'-linked conjugation resulting in MAVS proteasomal degradation. Involved in the regulation of apoptosis and reactive oxygen species levels through the ubiquitination and proteasomal degradation of TXNIP. Mediates the antiapoptotic activity of epidermal growth factor through the ubiquitination and proteasomal degradation of p15 BID. Targets DTX1 for lysosomal degradation and controls NOTCH1 degradation, in the absence of ligand, through 'Lys-29'-linked polyubiquitination. {ECO:0000250, ECO:0000269PubMed:14602072, ECO:0000269PubMed:16387660, ECO:0000269PubMed:17028573, ECO:0000269PubMed:18628966, ECO:0000269PubMed:18718448, ECO:0000269PubMed:18718449, ECO:0000269PubMed:19131965, ECO:0000269PubMed:19592251, ECO:0000269PubMed:19881509, ECO:0000269PubMed:20068034, ECO:0000269PubMed:20392206}.

Subcellular Localization

Cell membrane. Cytoplasm {ECO:0000250}. Nucleus. Note=Associates with endocytic vesicles. May be recruited to exosomes by NDFIP1.

Disease Associations

Syndromic multisystem autoimmune disease (SMAD) [MIM:613385]: A disorder characterized by organomegaly, failure to thrive, developmental delay, dysmorphic features and autoimmune inflammatory cell infiltration of the lungs, liver and gut. {ECO:0000269PubMed:20170897}. Note=The disease is caused by mutations affecting the gene represented in this entry.

Tissue Specificity

Widely expressed.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 211 experimentally validated interaction(s) in this database.
They are also associated with 16 interaction(s) predicted by orthology.

Experimentally validated
Total	211 [view]
Protein-Protein	210 [view]
Protein-DNA	0
Protein-RNA	1 [view]
DNA-DNA	0
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	16 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0004842	ubiquitin-protein transferase activity
GO:0005515	protein binding
GO:0043021	ribonucleoprotein complex binding
GO:0045236	CXCR chemokine receptor binding

Biological Process

GO:0001558	regulation of cell growth
GO:0006511	ubiquitin-dependent protein catabolic process
GO:0006915	apoptotic process
GO:0006954	inflammatory response
GO:0007219	Notch signaling pathway
GO:0016567	protein ubiquitination
GO:0032088	negative regulation of NF-kappaB transcription factor activity
GO:0032480	negative regulation of type I interferon production
GO:0035519	protein K29-linked ubiquitination
GO:0035872	nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway
GO:0042787	protein ubiquitination involved in ubiquitin-dependent protein catabolic process
GO:0043066	negative regulation of apoptotic process
GO:0045087	innate immune response (InnateDB)
GO:0046329	negative regulation of JNK cascade
GO:0046718	viral entry into host cell
GO:0050687	negative regulation of defense response to virus
GO:0051607	defense response to virus
GO:0070423	nucleotide-binding oligomerization domain containing signaling pathway
GO:0070534	protein K63-linked ubiquitination
GO:0070936	protein K48-linked ubiquitination
GO:0090085	regulation of protein deubiquitination