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Protein Page:
TNFAIP3 (human)
p Phosphorylation
ac Acetylation
me Methylation
m1 Mono-methylation
m2 Di-methylation
m3 Tri-methylation
ub Ubiquitylation
sm Sumoylation
ne Neddylation
gl O-GlcNAc
ga O-GalNAc
pa Palmitoylation
ad Adenylation
sn S-Nitrosylation
ca Caspase cleavage
sc Succinylation

Overview
TNFAIP3 Ubiquitin-editing enzyme that contains both ubiquitin ligase and deubiquitinase activities. Involved in immune and inflammatory responses signaled by cytokines, such as TNF-alpha and IL-1 beta, or pathogens via Toll-like receptors (TLRs) through terminating NF-kappa-B activity. Essential component of a ubiquitin-editing protein complex, comprising also RNF11, ITCH and TAX1BP1, that ensures the transient nature of inflammatory signaling pathways. In cooperation with TAX1BP1 promotes disassembly of E2-E3 ubiquitin protein ligase complexes in IL-1R and TNFR-1 pathways; affected are at least E3 ligases TRAF6, TRAF2 and BIRC2, and E2 ubiquitin-conjugating enzymes UBE2N and UBE2D3. In cooperation with TAX1BP1 promotes ubiquitination of UBE2N and proteasomal degradation of UBE2N and UBE2D3. Upon TNF stimulation, 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 NF-kappa-B. Deubiquinates TRAF6 probably acting on 'Lys-63'-linked polyubiquitin. Upon T-cell receptor (TCR)-mediated T-cell activation, deubiquitinates 'Lys-63'-polyubiquitin chains on MALT1 thereby mediating disassociation of the CBM (CARD11:BCL10:MALT1) and IKK complexes and preventing sustained IKK activation. Deubiquinates NEMO/IKBKG; the function is facilitated by TNIP1 and leads to inhibition of NF-kappa-B activation. Upon stimulation by bacterial peptidoglycans, probably deubiquitinates RIPK2. Can also inhibit I-kappa-B-kinase (IKK) through a non-catalytic mechanism which involves polyubiquitin; polyubiquitin promotes association with IKBKG and prevents IKK MAP3K7-mediated phosphorylation. Targets TRAF2 for lysosomal degradation. In vitro able to deubiquitinate both 'Lys-48'- and 'Lys-63' polyubiquitin chains. Inhibitor of programmed cell death. Has a role in the function of the lymphoid system. Homodimer. Interacts with TNIP1, TAX1BP1 and TRAF2. Interacts with RNF11, ITCH and TAX1BP1 only after TNF stimulation; these interaction are transient and they are lost after 1 hour of stimulation with TNF. Interacts with YWHAZ and YWHAH. Interacts with IKBKG; the interaction is induced by TNF stimulation and by polyubiquitin. Interacts with RIPK1. Interacts with UBE2N; the interaction requires TAX1BP1. Interacts with TRAF6; the interaction is inhibited by HTLV-1 protein Tax. By TNF. Belongs to the peptidase C64 family. Note: This description may include information from UniProtKB.
Protein type: Ubiquitin conjugating system; Apoptosis; EC 3.4.19.12; Protease
Chromosomal Location of Human Ortholog: 6q23
Cellular Component: cytoplasm; cytosol; lysosome; nucleus
Molecular Function: DNA binding; kinase binding; ligase activity; protease binding; protein binding; protein self-association; ubiquitin binding; ubiquitin-protein ligase activity; ubiquitin-specific protease activity; zinc ion binding
Biological Process: apoptosis; B-1 B cell homeostasis; inflammatory response; inhibition of NF-kappaB transcription factor; negative regulation of B cell activation; negative regulation of bone resorption; negative regulation of chronic inflammatory response; negative regulation of cyclin-dependent protein kinase activity; negative regulation of I-kappaB kinase/NF-kappaB cascade; negative regulation of inflammatory response; negative regulation of innate immune response; negative regulation of interferon type I production; negative regulation of interleukin-1 beta production; negative regulation of interleukin-2 production; negative regulation of interleukin-6 production; negative regulation of protein ubiquitination; negative regulation of smooth muscle cell proliferation; negative regulation of toll-like receptor 2 signaling pathway; negative regulation of toll-like receptor 3 signaling pathway; negative regulation of toll-like receptor 4 signaling pathway; negative regulation of toll-like receptor 5 signaling pathway; negative regulation of tumor necrosis factor production; positive regulation of protein catabolic process; protein deubiquitination; protein oligomerization; regulation of defense response to virus by host; regulation of germinal center formation; regulation of inflammatory response; response to molecule of bacterial origin; response to muramyl dipeptide
Reference #:  P21580 (UniProtKB)
Gene Symbols: TNFAIP3
Molecular weight: 89,614 Da
Basal Isoelectric point: 8.61  Predict pI for various phosphorylation states
CST Pathways:  Inhibition of Apoptosis  |  NF-kB Signaling  |  Toll-Like Receptor Signaling
Protein-Specific Antibodies or siRNAs from Cell Signaling Technology® Total Proteins
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TNFAIP3

Protein Structure Not Found.
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Sites Implicated In
ubiquitination: S381‑p, S480‑p, S565‑p, T625‑p

Modification Sites and Domains Show Modification Legend
Click here to view phosphorylation modifications only

Modification Sites in Parent Protein, Orthologs, and Isoforms Show Modification Legend
 

Show Multiple Sequence Alignment


 LTP 

LTP: The number of records in which this modification site was determined using site-specific methods. SS methods include amino acid sequencing, site-directed mutagenesis, modification site-specific antibodies, specific MS strategies, etc.


 HTP 

HTP: The number of records in which this modification site was assigned using ONLY proteomic discovery-mode mass spectrometry.


       human

 
0 19 K81‑ac QATLESQkkLNWCRE
0 10 K81‑ub QATLESQkkLNWCRE
0 1 K82‑ub ATLESQkkLNWCREV
0 1 T118‑p YMWGVQDtDLVLRkA
0 1 K124‑ub DtDLVLRkALFstLk
0 1 S128‑p VLRkALFstLkETDT
0 1 T129‑p LRkALFstLkETDTR
0 1 K131‑ub kALFstLkETDTRNF
0 1 T179‑p IKMASTDtPMARSGL
0 1 S220 KMLRSLESGSNFAPL
0 1 S222 LRSLESGSNFAPLKV
0 1 Y306‑p KEKLLKEyLMVIEIP
0 1 T321‑p VQGWDHGttHLINAA
0 1 T322‑p QGWDHGttHLINAAK
0 1 S376‑p AQNPMEPsVPQLsLM
2 5 S381‑p EPsVPQLsLMDVKCE
0 1 S423‑p NKLPKLNskPGPEGL
0 2 K424‑ub KLPKLNskPGPEGLP
0 1 T454‑p AWNPEEStGGPHsAP
0 3 S459‑p EStGGPHsAPPTAPs
0 2 S466‑p sAPPTAPsPFLFSET
1 1 S480‑p TTAMKCRsPGCPFTL
0 1 S507 NARQLHASHAPDHTR
0 1 A509 RQLHASHAPDHTRHL
0 4 K520‑ub TRHLDPGkCQACLQD
0 2 S537‑p RTFNGICsTCFkRTT
0 1 T538 TFNGICsTCFkRTTA
0 6 K541‑ub GICsTCFkRTTAEAS
0 1 T544 sTCFkRTTAEASSSL
0 1 S549 RTTAEASSSLSTSLP
0 1 S550 TTAEASSSLSTSLPP
0 1 S552 AEASSSLSTSLPPSC
1 1 S565‑p SCHQRSKsDPsRLVR
0 1 S568‑p QRSKsDPsRLVRsPs
0 5 S573‑p DPsRLVRsPsPHsCH
0 7 S575‑p sRLVRsPsPHsCHRA
0 2 S578‑p VRsPsPHsCHRAGND
0 6 A586 CHRAGNDAPAGCLsQ
0 1 A588 RAGNDAPAGCLsQAA
0 2 S592‑p DAPAGCLsQAARtPG
0 1 T597‑p CLsQAARtPGDRTGT
0 5 Y614‑p CRKAGCVyFGtPENk
0 2 T617‑p AGCVyFGtPENkGFC
0 2 K621‑ub yFGtPENkGFCtLCF
1 18 T625‑p PENkGFCtLCFIEyR
0 3 Y631‑p CtLCFIEyRENkHFA
0 1 K635‑ub FIEyRENkHFAAASG
0 19 K643‑ub HFAAASGkVsPtAsR
0 10 S645‑p AAASGkVsPtAsRFQ
0 1 T647‑p ASGkVsPtAsRFQNT
0 1 S649‑p GkVsPtAsRFQNTIP
0 2 Y673‑p GSTMFEGyCQkCFIE
0 1 K676‑ub MFEGyCQkCFIEAQN
0 3 S699‑p TEEQLRSsQRRDVPR
0 3 K715‑ub TQSTSRPkCARASCk
0 23 K722‑ub kCARASCkNILACRs
0 2 S729‑p kNILACRsEELCMEC
0 2 Y778‑p GNAKCNGyCNECFQF
  mouse

 
K81 QASLESQKKLNWCRE
K81 QASLESQKKLNWCRE
K82 ASLESQKKLNWCREV
T118 YMWGVQDTDLVLRKA
K124 DTDLVLRKALCSTLK
S128 VLRKALCSTLKETDT
T129 LRKALCSTLKETDTR
K131 KALCSTLKETDTRNF
T179 VKMASADTPAARSGL
S220‑p KMLRSLEsGsNFAPL
S222‑p LRSLEsGsNFAPLKV
Y306 KEKLLKEYLIVMEIP
T321 VQGWDHGTTHLINAA
T322 QGWDHGTTHLINAAK
S376 AQNPLEPSTPQLsLM
S381‑p EPSTPQLsLMDIKCE
S423 SKLPKLNSKLGPEGL
K424 KLPKLNSKLGPEGLP
A446 NWSPEETAGGPHSAP
S451 ETAGGPHSAPPTAPS
S458 SAPPTAPSLFLFSET
S472 TTAMKCRSPGCPFTL
S498‑p HARQINAsHtADPGK
T500‑p RQINAsHtADPGKCQ
K505 sHtADPGKCQACLQD
S522‑p RTFNGICstCFKRTt
T523‑p TFNGICstCFKRTtA
K526 GICstCFKRTtAEPS
T529‑p stCFKRTtAEPSssL
S534‑p RTtAEPSssLtSSIP
S535‑p TtAEPSssLtSSIPA
T537‑p AEPSssLtSSIPASC
S550‑p SCHQRSKsDPSQLIQ
S553 QRSKsDPSQLIQSLT
S558 DPSQLIQSLTPHSCH
T560 SQLIQSLTPHSCHRT
S563 IQSLTPHSCHRTGNV
S571‑p CHRTGNVsPsGCLsQ
S573‑p RTGNVsPsGCLsQAA
S577‑p VsPsGCLsQAARTPG
T582 CLsQAARTPGDRAGT
Y599 CRKAGCMYFGTPENK
T602 AGCMYFGTPENKGFC
K606 YFGTPENKGFCTLCF
T610 PENKGFCTLCFIEyR
Y616‑p CTLCFIEyRENKQSV
K620 FIEyRENKQSVTASE
K628 QSVTASEKAGsPAPR
S631‑p TASEKAGsPAPRFQN
P632 ASEKAGsPAPRFQNN
P634 EKAGsPAPRFQNNVP
Y658 GSTMFEGYCQKCFIE
K661 MFEGYCQKCFIEAQN
S684 TEEQLRSSQHRDMPR
K700 TQVASRLKCARASCK
K707 KCARASCKNILACRS
S714 KNILACRSEELCMEC
Y763 GNAKCNGYCNECYQF
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