Protein: E3 ubiquitin-protein ligase Itchy (EC 2.3.2.26) (HECT-type E3 ubiquitin transferase Itchy homolog) (Q8C863)
Organism: Mus musculus (Mouse)
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 (By similarity). Involved in the control of inflammatory signaling pathways (By similarity). 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 (By similarity). Promotes the association of the complex after TNF stimulation (By similarity). Once the complex is formed, TNFAIP3 deubiquitinates 'Lys-63' polyubiquitin chains on RIPK1 and catalyzes the formation of 'Lys-48'-polyubiquitin chains (By similarity). This leads to RIPK1 proteasomal degradation and consequently termination of the TNF- or LPS-mediated activation of NFKB1 (By similarity). Ubiquitinates RIPK2 by 'Lys-63'-linked conjugation and influences NOD2-dependent signal transduction pathways (By similarity). Regulates the transcriptional activity of several transcription factors involved in immune response. Ubiquitinates NFE2 by 'Lys-63' linkages and is implicated in the control of the development of hematopoietic lineages (By similarity). Mediates JUN ubiquitination and degradation. Mediates JUNB ubiquitination and degradation. Critical regulator of type 2 helper T (Th2) cell cytokine production by inducing JUNB ubiquitination and degradation. Involved in the negative regulation of MAVS-dependent cellular antiviral responses (By similarity). Ubiquitinates MAVS through 'Lys-48'-linked conjugation resulting in MAVS proteasomal degradation (By similarity). Following ligand stimulation, regulates sorting of Wnt receptor FZD4 to the degradative endocytic pathway probably by modulating PI42KA activity (By similarity). Ubiquitinates PI4K2A and negatively regulates its catalytic activity (By similarity). Ubiquitinates chemokine receptor CXCR4 and regulates sorting of CXCR4 to the degradative endocytic pathway following ligand stimulation by ubiquitinating endosomal sorting complex required for transport ESCRT-0 components HGS and STAM (By similarity). Targets DTX1 for lysosomal degradation and controls NOTCH1 degradation, in the absence of ligand, through 'Lys-29'-linked polyubiquitination. Ubiquitinates SNX9 (By similarity). Ubiquitinates MAP3K7 through 'Lys-48'-linked conjugation. Involved in the regulation of apoptosis and reactive oxygen species levels through the ubiquitination and proteasomal degradation of TXNIP (By similarity). Mediates the antiapoptotic activity of epidermal growth factor through the ubiquitination and proteasomal degradation of p15 BID. Ubiquitinates BRAT1 and this ubiquitination is enhanced in the presence of NDFIP1 (By similarity). Ubiquitinates NEDD9/HEF1, resulting in proteosomal degradation of NEDD9/HEF1 (By similarity).
Subcellular location: Cell membrane {ECO:0000250|UniProtKB:Q96J02}; Peripheral membrane protein {ECO:0000250|UniProtKB:Q96J02}; Cytoplasmic side {ECO:0000250|UniProtKB:Q96J02}. Cytoplasm {ECO:0000250|UniProtKB:Q96J02}. Nucleus {ECO:0000250|UniProtKB:Q96J02}. Early endosome membrane {ECO:0000250|UniProtKB:Q96J02}; Peripheral membrane protein {ECO:0000250|UniProtKB:Q96J02}; Cytoplasmic side {ECO:0000250|UniProtKB:Q96J02}. Endosome membrane {ECO:0000250|UniProtKB:Q96J02}; Peripheral membrane protein {ECO:0000250|UniProtKB:Q96J02}; Cytoplasmic side {ECO:0000250|UniProtKB:Q96J02}. Note=May be recruited to exosomes by NDFIP1. Localizes to plasma membrane upon CXCL12 stimulation where it co-localizes with CXCL4. Localization to early endosomes is increased upon CXCL12 stimulation where it co-localizes with DTX3L and CXCL4. {ECO:0000250|UniProtKB:Q96J02}.
Sequence: MSDSGPQLDSMGSLTMKSQLQITVISAKLKENKKNWFGPSPYVEVTVDGQSKKTEKCNNTNSPKWKQPLTVIVTPTSKLCFRVWSHQTLKSDVLLGTAGLDIYETLKSNNMKLEEVVMTLQLVGDKEPTETMGDLSVCLDGLQVEAEVVTNGETSCSESTTQNDDGCRTRDDTRVSTNGSEDPEVAASGENKRANGNNSPSLSNGGFKPSRPPRPSRPPPPTPRRPASVNGSPSTNSDSDGSSTGSLPPTNTNVNTSTSEGATSGLIIPLTISGGSGPRPLNTVSQAPLPPGWEQRVDQHGRVYYVDHVEKRTTWDRPEPLPPGWERRVDNMGRIYYVDHFTRTTTWQRPTLESVRNYEQWQLQRSQLQGAMQQFNQRFIYGNQDLFATSQNKEFDPLGPLPPGWEKRTDSNGRVYFVNHNTRITQWEDPRSQGQLNEKPLPEGWEMRFTVDGIPYFVDHNRRATTYIDPRTGKSALDNGPQIAYVRDFKAKVQYFRFWCQQLAMPQHIKITVTRKTLFEDSFQQIMSFSPQDLRRRLWVIFPGEEGLDYGGVAREWFFLLSHEVLNPMYCLFEYAGKDNYCLQINPASYINPDHLKYFRFIGRFIAMALFHGKFIDTGFSLPFYKRILNKPVGLKDLESIDPEFYNSLIWVKENNIEECGLEMYFSVDKEILGEIKSHDLKPNGGNILVTEENKEEYIRMVAEWRLSRGVEEQTQAFFEGFNEILPQQYLQYFDAKELEVLLCGMQEIDLNDWQRHAIYRHYTRTSKQIMWFWQFVKEIDNEKRMRLLQFVTGTCRLPVGGFADLMGSNGPQKFCIEKVGKENWLPRSHTCFNRLDLPPYKSYEQLKEKLLFAIEETEGFGQE
InterPro domains: - IPR035892: C2 domain superfamily (homologous_superfamily) [13-155]
- IPR000569: HECT domain (domain) [509-864]
- IPR001202: WW domain (domain) [287-472]
- IPR024928: E3 ubiquitin-protein ligase, SMURF1 type (family) [6-864]
- IPR000008: C2 domain (domain) [1-115]
- IPR050409: E3 ubiquitin-protein ligase (family) [57-862]
- IPR035983: HECT, E3 ligase catalytic domain (homologous_superfamily) [491-858]
- IPR036020: WW domain superfamily (homologous_superfamily) [286-471]
Interaction partners: - Protein numb homolog
- CASP8 and FADD-like apoptosis regulator
- RING finger protein 11
- Tax1-binding protein 1 homolog
- Ubiquitin carboxyl-terminal hydrolase CYLD
- TNF receptor-associated factor 6
- Stress-activated protein kinase JNK
- Mitogen-activated protein kinase 9
- Ubiquitin-ribosomal protein eS31 fusion protein
- Mitogen-activated protein kinase 10
Gene Ontology annotations:
Molecular Function (MF): GO:0003674 (molecular function), GO:0005488 (binding), GO:0003824 (catalytic activity), GO:0016740 (transferase activity), GO:0140096 (catalytic activity, acting on a protein), GO:0005515 (protein binding), GO:0019787 (ubiquitin-like protein transferase activity), GO:0004842 (ubiquitin-protein transferase activity), GO:0061659 (ubiquitin-like protein ligase activity), GO:0061630 (ubiquitin protein ligase activity)
Biological Process (BP): GO:0008150 (biological process), GO:0008152 (metabolic process), GO:0048518 (positive regulation of biological process), GO:0050789 (regulation of biological process), GO:0044419 (biological process involved in interspecies interaction between organisms), GO:0002376 (immune system process), GO:0032501 (multicellular organismal process), GO:0065007 (biological regulation), GO:0050896 (response to stimulus), GO:0032502 (developmental process), GO:0009987 (cellular process), GO:0048519 (negative regulation of biological process), GO:0009605 (response to external stimulus), GO:0048869 (cellular developmental process), GO:0048856 (anatomical structure development), GO:0007275 (multicellular organism development), GO:0001775 (cell activation), GO:0009653 (anatomical structure morphogenesis), GO:0045321 (leukocyte activation), GO:0019222 (regulation of metabolic process), GO:0006955 (immune response), GO:0006807 (nitrogen compound metabolic process), GO:0071704 (organic substance metabolic process), GO:0048646 (anatomical structure formation involved in morphogenesis), GO:0009056 (catabolic process), GO:0044237 (cellular metabolic process), GO:0009607 (response to biotic stimulus), GO:0050794 (regulation of cellular process), GO:0009893 (positive regulation of metabolic process), GO:0006950 (response to stress), GO:0048523 (negative regulation of cellular process), GO:0051707 (response to other organism), GO:0044238 (primary metabolic process), GO:0048522 (positive regulation of cellular process), GO:1901564 (organonitrogen compound metabolic process), GO:0043207 (response to external biotic stimulus), GO:0010604 (positive regulation of macromolecule metabolic process), GO:0048468 (cell development), GO:0030154 (cell differentiation), GO:0044248 (cellular catabolic process), GO:0048731 (system development), GO:0019538 (protein metabolic process), GO:0048513 (animal organ development), GO:0006952 (defense response), GO:0060255 (regulation of macromolecule metabolic process), GO:0043170 (macromolecule metabolic process), GO:0046649 (lymphocyte activation), GO:0098542 (defense response to other organism), GO:0035295 (tube development), GO:0009894 (regulation of catabolic process), GO:0009887 (animal organ morphogenesis), GO:0048598 (embryonic morphogenesis), GO:0009888 (tissue development), GO:0031325 (positive regulation of cellular metabolic process), GO:0009617 (response to bacterium), GO:0051171 (regulation of nitrogen compound metabolic process), GO:0051173 (positive regulation of nitrogen compound metabolic process), GO:0009790 (embryo development), GO:0031323 (regulation of cellular metabolic process), GO:0080090 (regulation of primary metabolic process), GO:1901575 (organic substance catabolic process), GO:0044260 (cellular macromolecule metabolic process), GO:0009896 (positive regulation of catabolic process), GO:0035239 (tube morphogenesis), GO:0030097 (hemopoiesis), GO:1901565 (organonitrogen compound catabolic process), GO:0006508 (proteolysis), GO:0042176 (regulation of protein catabolic process), GO:0051246 (regulation of protein metabolic process), GO:0048562 (embryonic organ morphogenesis), GO:0030163 (protein catabolic process), GO:0042476 (odontogenesis), GO:0030334 (regulation of cell migration), GO:0036211 (protein modification process), GO:0009057 (macromolecule catabolic process), GO:0030324 (lung development), GO:0030323 (respiratory tube development), GO:0043412 (macromolecule modification), GO:0048514 (blood vessel morphogenesis), GO:0044265 (cellular macromolecule catabolic process), GO:0072359 (circulatory system development), GO:0060541 (respiratory system development), GO:0051247 (positive regulation of protein metabolic process), GO:0045732 (positive regulation of protein catabolic process), GO:0031331 (positive regulation of cellular catabolic process), GO:0031329 (regulation of cellular catabolic process), GO:0048565 (digestive tract development), GO:0009792 (embryo development ending in birth or egg hatching), GO:0060541 (respiratory system development), GO:0043009 (chordate embryonic development), GO:0030162 (regulation of proteolysis), GO:0001892 (embryonic placenta development), GO:0070647 (protein modification by small protein conjugation or removal), GO:0043632 (modification-dependent macromolecule catabolic process), GO:0051603 (proteolysis involved in protein catabolic process), GO:0048706 (embryonic skeletal system development), GO:0045862 (positive regulation of proteolysis), GO:1901800 (positive regulation of proteasomal protein catabolic process), GO:2000060 (positive regulation of ubiquitin-dependent protein catabolic process), GO:0061136 (regulation of proteasomal protein catabolic process), GO:2000058 (regulation of ubiquitin-dependent protein catabolic process), GO:0001701 (in utero embryonic development), GO:1903052 (positive regulation of proteolysis involved in protein catabolic process), GO:0032434 (regulation of proteasomal ubiquitin-dependent protein catabolic process), GO:0043161 (proteasome-mediated ubiquitin-dependent protein catabolic process), GO:1903050 (regulation of proteolysis involved in protein catabolic process), GO:0032446 (protein modification by small protein conjugation), GO:0032436 (positive regulation of proteasomal ubiquitin-dependent protein catabolic process), GO:0019941 (modification-dependent protein catabolic process), GO:0006511 (ubiquitin-dependent protein catabolic process), GO:0016567 (protein ubiquitination), GO:0006513 (protein monoubiquitination), GO:0000209 (protein polyubiquitination), GO:0070534 (protein K63-linked ubiquitination)
Cellular Component (CC): GO:0005575 (cellular component), GO:0110165 (cellular anatomical entity), GO:0005737 (cytoplasm), GO:0005829 (cytosol), GO:0005622 (intracellular anatomical structure)