Names & Taxonomy
- Uniprot ID:
- Q96J02
- Entry Name:
- ITCH_HUMAN
- Status:
- reviewed
- Protein Names:
- E3 ubiquitin-protein ligase Itchy homolog (Itch) (EC 6.3.2.-) (Atrophin-1-interacting protein 4) (AIP4) (NFE2-associated polypeptide 1) (NAPP1)
- Gene Names:
- ITCH
- Gene Names Primary:
- ITCH
- Organism:
- Homo sapiens (Human)
Structure
- Length:
- 903
- Sequence:
- MSDSGSQLGSMGSLTMKSQLQITVISAKLKENKKNWFGPSPYVEVTVDGQSKKTEKCNNTNSPKWKQPLTVIVTPVSKLHFRVWSHQTLKSDVLLGTAALDIYETLKSNNMKLEEVVVTLQLGGDKEPTETIGDLSICLDGLQLESEVVTNGETTCSENGVSLCLPRLECNSAISAHCNLCLPGLSDSPISASRVAGFTGASQNDDGSRSKDETRVSTNGSDDPEDAGAGENRRVSGNNSPSLSNGGFKPSRPPRPSRPPPPTPRRPASVNGSPSATSESDGSSTGSLPPTNTNTNTSEGATSGLIIPLTISGGSGPRPLNPVTQAPLPPGWEQRVDQHGRVYYVDHVEKRTTWDRPEPLPPGWERRVDNMGRIYYVDHFTRTTTWQRPTLESVRNYEQWQLQRSQLQGAMQQFNQRFIYGNQDLFATSQSKEFDPLGPLPPGWEKRTDSNGRVYFVNHNTRITQWEDPRSQGQLNEKPLPEGWEMRFTVDGIPYFVDHNRRTTTYIDPRTGKSALDNGPQIAYVRDFKAKVQYFRFWCQQLAMPQHIKITVTRKTLFEDSFQQIMSFSPQDLRRRLWVIFPGEEGLDYGGVAREWFFLLSHEVLNPMYCLFEYAGKDNYCLQINPASYINPDHLKYFRFIGRFIAMALFHGKFIDTGFSLPFYKRILNKPVGLKDLESIDPEFYNSLIWVKENNIEECDLEMYFSVDKEILGEIKSHDLKPNGGNILVTEENKEEYIRMVAEWRLSRGVEEQTQAFFEGFNEILPQQYLQYFDAKELEVLLCGMQEIDLNDWQRHAIYRHYARTSKQIMWFWQFVKEIDNEKRMRLLQFVTGTCRLPVGGFADLMGSNGPQKFCIEKVGKENWLPRSHTCFNRLDLPPYKSYEQLKEKLLFAIEETEGFGQE
- Proteomes:
- UP000005640
Subcellular location
- Subcellular Location:
- Cell membrane. Cytoplasm
Function
- 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. Ubiquitinates BRAT1 and this ubiquitination is enhanced in the presence of NDFIP1 (PubMed:25631046).
- Pathway:
- Protein modification; protein ubiquitination.
- Enzyme Regulation:
- ENZYME REGULATION: Activated by NDFIP1- and NDFIP2-binding.
- Active Site:
- ACT_SITE 871 871 Glycyl thioester intermediate.
- Gene Ontology Go:
- cell cortex
cytoplasm
cytoplasmic vesicle
cytosol
extracellular exosome
membrane
nucleus
plasma membrane
CXCR chemokine receptor binding
ligase activity
ribonucleoprotein complex binding
ubiquitin protein ligase activity
ubiquitin-protein transferase activity
apoptotic process
defense response to virus
inflammatory response
innate immune response
negative regulation of alpha-beta T cell proliferation
negative regulation of apoptotic process
negative regulation of defense response to virus
negative regulation of JNK cascade
negative regulation of NF-kappaB transcription factor activity
negative regulation of type I interferon production
Notch signaling pathway
nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway
nucleotide-binding oligomerization domain containing signaling pathway
positive regulation of protein catabolic process
positive regulation of T cell anergy
protein K29-linked ubiquitination
protein K48-linked ubiquitination
protein K63-linked ubiquitination
protein ubiquitination
protein ubiquitination involved in ubiquitin-dependent protein catabolic process
regulation of cell growth
regulation of protein deubiquitination
ubiquitin-dependent protein catabolic process
viral entry into host cell - Gene Ontology Biological Process:
- apoptotic process
defense response to virus
inflammatory response
innate immune response
negative regulation of alpha-beta T cell proliferation
negative regulation of apoptotic process
negative regulation of defense response to virus
negative regulation of JNK cascade
negative regulation of NF-kappaB transcription factor activity
negative regulation of type I interferon production
Notch signaling pathway
nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway
nucleotide-binding oligomerization domain containing signaling pathway
positive regulation of protein catabolic process
positive regulation of T cell anergy
protein K29-linked ubiquitination
protein K48-linked ubiquitination
protein K63-linked ubiquitination
protein ubiquitination
protein ubiquitination involved in ubiquitin-dependent protein catabolic process
regulation of cell growth
regulation of protein deubiquitination
ubiquitin-dependent protein catabolic process
viral entry into host cell - Gene Ontology Molecular Function:
- CXCR chemokine receptor binding
ligase activity
ribonucleoprotein complex binding
ubiquitin protein ligase activity
ubiquitin-protein transferase activity - Gene Ontology Cellular Component:
- cell cortex
cytoplasm
cytoplasmic vesicle
cytosol
extracellular exosome
membrane
nucleus
plasma membrane - Keywords:
- 3D-structure
Acetylation
Alternative splicing
Antiviral defense
Apoptosis
Cell membrane
Complete proteome
Cytoplasm
Direct protein sequencing
Host-virus interaction
Immunity
Innate immunity
Ligase
Membrane
Nucleus
Phosphoprotein
Reference proteome
Repeat
Ubl conjugation
Ubl conjugation pathway - Interacts With:
- P70444; Q9NQC7; P08151; P13285; Q9QZS3-2; Q9BTU6; Q9Y3C5; Q96BR1; Q9Y5X1; Q13625; O15350-1; O15350-8
Publication
- PubMed ID:
- 11318614 14702039 11780052 15489334 9647693 11046148 12226085 14559117 14602072 16888620 17028573 16387660 18718448 18718449 18819914 18628966 19413330 19580544 19592251 19131965 19116316 19881509 20170897 20491914 20392206 20068034 20858735 21269460 23146885 22179831 23236378 25631046 17652093