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   24-JAN-2024, entry version 89.
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}.
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DR   EMBL; AB168334; BAE00458.1; -; mRNA.
DR   RefSeq; NP_001270745.1; NM_001283816.1.
DR   AlphaFoldDB; Q4R8W3; -.
DR   SMR; Q4R8W3; -.
DR   STRING; 9541.ENSMFAP00000045359; -.
DR   MEROPS; C64.003; -.
DR   eggNOG; KOG4345; Eukaryota.
DR   OrthoDB; 2909231at2759; -.
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 canonical NF-kappaB signal transduction; 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   GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR   CDD; cd22766; OTU_TNFAIP3; 1.
DR   Gene3D; 1.20.5.4770; -; 1.
DR   Gene3D; 3.90.70.80; -; 1.
DR   Gene3D; 4.10.240.30; -; 3.
DR   InterPro; IPR003323; OTU_dom.
DR   InterPro; IPR002653; Znf_A20.
DR   PANTHER; PTHR13367:SF3; TUMOR NECROSIS FACTOR ALPHA-INDUCED PROTEIN 3; 1.
DR   PANTHER; PTHR13367; UBIQUITIN THIOESTERASE; 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 proteasomal 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
//