Inhibition of NF-kappaB signaling by A20 through disruption of ubiquitin enzyme complexes.
A20 negatively regulates inflammation by inhibiting the nuclear factor kappaB (NF-kappaB) transcription factor in the tumor necrosis factor-receptor (TNFR) and Toll-like receptor (TLR) pathways. A20 contains deubiquitinase and E3 ligase domains and thus has been proposed to function as a ubiquitin-editing enzyme downstream of TNFR1 by inactivating ubiquitinated RIP1. However, it remains unclear how A20 terminates NF-kappaB signaling downstream of TLRs. We have shown that A20 inhibited the E3 ligase activities of TRAF6, TRAF2, and cIAP1 by antagonizing interactions with the E2 ubiquitin conjugating enzymes Ubc13 and UbcH5c. A20, together with the regulatory molecule TAX1BP1, interacted with Ubc13 and UbcH5c and triggered their ubiquitination and proteasome-dependent degradation. These findings suggest mechanism of A20 action in the inhibition of inflammatory signaling pathways.
Shembade
Noula
N
Department of Microbiology and Immunology, Sylvester Comprehensive Cancer Center, The University of Miami, Miller School of Medicine, Miami, FL 33136, USA. nshembade@med.miami.edu
Ma
Averil
A
Harhaj
Edward W
EW
D020816:Amino Acid Motifs; D000818:Animals; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016356:Gene Products, tax / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism*; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D007375:Interleukin-1 / Q000276:immunology / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D057149:Ubiquitinated Proteins / Q000378:metabolism; D054875:Ubiquitination; D016335:Zinc Fingers
D016356:Gene Products, tax; D051034:Inhibitor of Apoptosis Proteins; D007375:Interleukin-1; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D047888:Receptors, Tumor Necrosis Factor, Type I; C523855:TAX1BP1 protein, mouse; D047992:TNF Receptor-Associated Factor 2; D048029:TNF Receptor-Associated Factor 6; D014409:Tumor Necrosis Factor-alpha; D057149:Ubiquitinated Proteins; C514970:tax protein, Human T-lymphotrophic virus 1; C514982:Ube2n protein, mouse; D044763:Ubiquitin-Conjugating Enzymes; D044767:Ubiquitin-Protein Ligases; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506251:Ripk1 protein, mouse; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse; D046988:Proteasome Endopeptidase Complex