TNAP3_MACFA
ID TNAP3_MACFA Reviewed; 790 AA.
AC Q4R8W3;
DT 24-JAN-2006, integrated into UniProtKB/Swiss-Prot.
DT 19-JUL-2005, sequence version 1.
DT 03-AUG-2022, entry version 83.
DE RecName: Full=Tumor necrosis factor alpha-induced protein 3;
DE Short=TNF alpha-induced protein 3;
DE EC=2.3.2.-;
DE EC=3.4.19.12;
DE Contains:
DE RecName: Full=A20p50;
DE Contains:
DE RecName: Full=A20p37;
GN Name=TNFAIP3; ORFNames=QtsA-11293;
OS Macaca fascicularis (Crab-eating macaque) (Cynomolgus monkey).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini;
OC Cercopithecidae; Cercopithecinae; Macaca.
OX NCBI_TaxID=9541;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Testis;
RG International consortium for macaque cDNA sequencing and analysis;
RT "DNA sequences of macaque genes expressed in brain or testis and its
RT evolutionary implications.";
RL Submitted (JUN-2005) to the EMBL/GenBank/DDBJ databases.
CC -!- FUNCTION: Ubiquitin-editing enzyme that contains both ubiquitin ligase
CC and deubiquitinase activities. Involved in immune and inflammatory
CC responses signaled by cytokines, such as TNF-alpha and IL-1 beta, or
CC pathogens via Toll-like receptors (TLRs) through terminating NF-kappa-B
CC activity. Essential component of a ubiquitin-editing protein complex,
CC comprising also RNF11, ITCH and TAX1BP1, that ensures the transient
CC nature of inflammatory signaling pathways. In cooperation with TAX1BP1
CC promotes disassembly of E2-E3 ubiquitin protein ligase complexes in IL-
CC 1R and TNFR-1 pathways; affected are at least E3 ligases TRAF6, TRAF2
CC and BIRC2, and E2 ubiquitin-conjugating enzymes UBE2N and UBE2D3. In
CC cooperation with TAX1BP1 promotes ubiquitination of UBE2N and
CC proteasomal degradation of UBE2N and UBE2D3. Upon TNF stimulation,
CC deubiquitinates 'Lys-63'-polyubiquitin chains on RIPK1 and catalyzes
CC the formation of 'Lys-48'-polyubiquitin chains. This leads to RIPK1
CC proteasomal degradation and consequently termination of the TNF- or
CC LPS-mediated activation of NF-kappa-B. Deubiquitinates TRAF6 probably
CC acting on 'Lys-63'-linked polyubiquitin. Upon T-cell receptor (TCR)-
CC mediated T-cell activation, deubiquitinates 'Lys-63'-polyubiquitin
CC chains on MALT1 thereby mediating disassociation of the CBM
CC (CARD11:BCL10:MALT1) and IKK complexes and preventing sustained IKK
CC activation. Deubiquitinates NEMO/IKBKG; the function is facilitated by
CC TNIP1 and leads to inhibition of NF-kappa-B activation. Upon
CC stimulation by bacterial peptidoglycans, probably deubiquitinates
CC RIPK2. Can also inhibit I-kappa-B-kinase (IKK) through a non-catalytic
CC mechanism which involves polyubiquitin; polyubiquitin promotes
CC association with IKBKG and prevents IKK MAP3K7-mediated
CC phosphorylation. Targets TRAF2 for lysosomal degradation. In vitro able
CC to deubiquitinate 'Lys-11'-, 'Lys-48'- and 'Lys-63' polyubiquitin
CC chains. Inhibitor of programmed cell death. Has a role in the function
CC of the lymphoid system. Required for LPS-induced production of pro-
CC inflammatory cytokines and IFN beta in LPS-tolerized macrophages (By
CC similarity). {ECO:0000250}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Thiol-dependent hydrolysis of ester, thioester, amide, peptide
CC and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-
CC residue protein attached to proteins as an intracellular targeting
CC signal).; EC=3.4.19.12;
CC -!- SUBUNIT: Homodimer. Interacts with TNIP1, TAX1BP1 and TRAF2. Interacts
CC with RNF11, ITCH and TAX1BP1 only after TNF stimulation; these
CC interaction are transient and they are lost after 1 hour of stimulation
CC with TNF (By similarity). Interacts with YWHAZ and YWHAH. Interacts
CC with IKBKG; the interaction is induced by TNF stimulation and by
CC polyubiquitin. Interacts with RIPK1. Interacts with UBE2N; the
CC interaction requires TAX1BP1. Interacts with TRAF6 (By similarity).
CC {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. Nucleus {ECO:0000250}.
CC Lysosome {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: [A20p50]: Cytoplasm {ECO:0000250}.
CC -!- DOMAIN: The A20-type zinc fingers mediate the ubiquitin ligase
CC activity. The A20-type zinc finger 4 selectively recognizes 'Lys-63'-
CC linked polyubiquitin. The A20-type zinc finger 4-7 are sufficient to
CC bind polyubiquitin (By similarity). {ECO:0000250}.
CC -!- DOMAIN: The OTU domain mediates the deubiquitinase activity.
CC {ECO:0000250}.
CC -!- PTM: Proteolytically cleaved by MALT1 upon TCR stimulation; disrupts
CC NF-kappa-B inhibitory function and results in increased IL-2
CC production. It is proposed that only a fraction of TNFAIP3 colocalized
CC with TCR and CBM complex is cleaved, leaving the main TNFAIP3 pool
CC intact (By similarity). {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the peptidase C64 family. {ECO:0000305}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; AB168334; BAE00458.1; -; mRNA.
DR RefSeq; NP_001270745.1; NM_001283816.1.
DR AlphaFoldDB; Q4R8W3; -.
DR SMR; Q4R8W3; -.
DR STRING; 9541.XP_005552014.1; -.
DR MEROPS; C64.003; -.
DR GeneID; 101867362; -.
DR CTD; 7128; -.
DR eggNOG; KOG4345; Eukaryota.
DR OrthoDB; 728724at2759; -.
DR Proteomes; UP000233100; Unplaced.
DR GO; GO:0005764; C:lysosome; IEA:UniProtKB-SubCell.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0004843; F:cysteine-type deubiquitinase activity; ISS:UniProtKB.
DR GO; GO:0003677; F:DNA binding; IEA:UniProtKB-KW.
DR GO; GO:0004842; F:ubiquitin-protein transferase activity; ISS:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0070301; P:cellular response to hydrogen peroxide; ISS:UniProtKB.
DR GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW.
DR GO; GO:0043124; P:negative regulation of I-kappaB kinase/NF-kappaB signaling; ISS:UniProtKB.
DR GO; GO:0050728; P:negative regulation of inflammatory response; ISS:UniProtKB.
DR GO; GO:0045824; P:negative regulation of innate immune response; ISS:UniProtKB.
DR GO; GO:0035871; P:protein K11-linked deubiquitination; ISS:UniProtKB.
DR GO; GO:0071108; P:protein K48-linked deubiquitination; ISS:UniProtKB.
DR GO; GO:0070936; P:protein K48-linked ubiquitination; ISS:UniProtKB.
DR GO; GO:0070536; P:protein K63-linked deubiquitination; ISS:UniProtKB.
DR InterPro; IPR033478; A20.
DR InterPro; IPR003323; OTU_dom.
DR InterPro; IPR002653; Znf_A20.
DR PANTHER; PTHR13367:SF3; PTHR13367:SF3; 1.
DR Pfam; PF02338; OTU; 1.
DR Pfam; PF01754; zf-A20; 5.
DR SMART; SM00259; ZnF_A20; 7.
DR PROSITE; PS50802; OTU; 1.
DR PROSITE; PS51036; ZF_A20; 7.
PE 2: Evidence at transcript level;
KW Acetylation; Apoptosis; Cytoplasm; DNA-binding; Hydrolase;
KW Inflammatory response; Lysosome; Metal-binding; Multifunctional enzyme;
KW Nucleus; Phosphoprotein; Protease; Reference proteome; Repeat;
KW Thiol protease; Transferase; Ubl conjugation pathway; Zinc; Zinc-finger.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000250|UniProtKB:P21580"
FT CHAIN 2..790
FT /note="Tumor necrosis factor alpha-induced protein 3"
FT /id="PRO_0000188792"
FT CHAIN 2..439
FT /note="A20p50"
FT /id="PRO_0000418129"
FT CHAIN 440..790
FT /note="A20p37"
FT /id="PRO_0000418130"
FT DOMAIN 92..263
FT /note="OTU"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00139"
FT ZN_FING 381..416
FT /note="A20-type 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT ZN_FING 472..507
FT /note="A20-type 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT ZN_FING 515..548
FT /note="A20-type 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT ZN_FING 601..636
FT /note="A20-type 4"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT ZN_FING 651..686
FT /note="A20-type 5"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT ZN_FING 710..745
FT /note="A20-type 6"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT ZN_FING 756..790
FT /note="A20-type 7"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT REGION 58..300
FT /note="TRAF-binding"
FT /evidence="ECO:0000250"
FT REGION 157..159
FT /note="Interaction with ubiquitin"
FT /evidence="ECO:0000250"
FT REGION 190..192
FT /note="Interaction with ubiquitin"
FT /evidence="ECO:0000250"
FT REGION 224..227
FT /note="Interaction with ubiquitin"
FT /evidence="ECO:0000250"
FT REGION 369..775
FT /note="Interaction with TNIP1"
FT /evidence="ECO:0000250"
FT REGION 386..453
FT /note="Interaction with RIPK1"
FT /evidence="ECO:0000250"
FT REGION 415..467
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 550..580
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 605..655
FT /note="Required for proteosomal degradation of UBE2N and
FT UBE2D3, TRAF6 deubiquitination, and TAX1BP1 interaction
FT with UBE2N"
FT /evidence="ECO:0000250"
FT REGION 606..790
FT /note="Sufficient for inhibitory activity of TNF-induced
FT NF-kappa-B activity"
FT /evidence="ECO:0000250"
FT REGION 689..712
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 697..790
FT /note="Required for lysosomal localization and for TRAF2
FT lysosomal degradation"
FT /evidence="ECO:0000250"
FT COMPBIAS 550..575
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 100
FT /evidence="ECO:0000250"
FT ACT_SITE 103
FT /note="Nucleophile"
FT /evidence="ECO:0000250"
FT ACT_SITE 256
FT /note="Proton acceptor"
FT /evidence="ECO:0000250"
FT BINDING 387
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 392
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 404
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 407
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 478
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 483
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 495
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 498
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 521
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 524
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 536
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 539
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 607
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="4"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 612
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="4"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 624
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="4"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 627
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="4"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 657
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="5"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 662
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="5"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 674
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="5"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 677
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="5"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 716
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="6"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 721
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="6"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 733
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="6"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 736
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="6"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 762
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="7"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 767
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="7"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 779
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="7"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 782
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="7"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT SITE 439..440
FT /note="Cleavage; by MALT1"
FT /evidence="ECO:0000250"
FT MOD_RES 2
FT /note="N-acetylalanine"
FT /evidence="ECO:0000250|UniProtKB:P21580"
FT MOD_RES 459
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P21580"
FT MOD_RES 575
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P21580"
FT MOD_RES 645
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P21580"
SQ SEQUENCE 790 AA; 89534 MW; EF112EDE0D4F40E9 CRC64;
MAEQVLPQAL YLSNMRKAVK IRERTPEDIF KPTNGIIHHF KTMHRYTLEM FRTCQFCPQF
REIIHKALID KNIQASLESQ KKLNWCREVR KLVALKTNGD GNCLMHATSQ YMWGVQDTDL
VLRKALFSTL KETDTRNFKF RWQLESLKSQ EFVETGLCYD TRNWNDEWDN LIKMASTDTP
MARSGLQYNS LEEIHIFVLC NILRRPIIVI SDKMLRSLES GSNFAPLKVG GIYLPLHWPA
QECYRYPIVL GYDSHHFVPL VTLKDSGPEI RAVPLVNRDR GRFEDLKVHF LTDPENEMKE
KLLKEYLMVI EIPVQGWDHG TTHLINAAKL DEANLPKEIN LVDDYFELVQ HEYKKWQENS
EQGRSEMHAQ NPMESSLPQL SLMDVKCETP NCPFFMSVNT QPLCHECSER RQKNQNKLPK
LNSKPGPEGL PGMALGASRG EAYEPLAWNP EEPTGGPHSA PPTAPSPFLF SETTAMKCRS
PGCPFTLNVQ HNGFCERCHN ARQLHASHAA DHTRHLDPGK CQACLQDVTR TFNGICSTCF
KRTTAEASSS LSTSLPPSCH QRSKSDPSQL VRSPSPHSCH RAGNDAPAGC LSQAARTPGD
RTGTSKCRKA GCMYFGTPEN KGFCTLCFIE YRENKHLVAA SGKASPTASR FQNTIPCLGR
ECGTLGSTMF EGYCQKCFIE AQNQRFHEAK RTEEQLRSSQ RRDVPRTTQS TSRPKCARAS
CKNILACRSE ELCMECQHPN PRMGPGAHRG EPAPEDPPKQ RCWAPACDHF GNAKCNGYCN
ECFQFKQMYG
