Inhibition of NF-κB Signaling by A20 Through Disruption of Ubiquitin Enzyme Complexes

By Noula Shembade, A. Ma, E. Harhaj. Science, 2010

644 citations recorded by the source corpus.

Limiting Inflammatory Signaling Dysregulation of the transcription factor NF-κB causes chronic inflammation, autoimmunity, and malignancy. The zinc-finger protein, A20, is vital for regulating NF-κB signaling, so much so that mice lacking A20 die young of multiorgan failure and cachexia. Similar deficiencies have been seen in Crohn's disease, rheumatoid arthritis, and other inflammatory diseases of humans. But how A20 works has remained unknown. Shembade et al. (p. 1135; see the Perspective by Sriskantharajah and Ley) have discovered that the A20 protein acts through the ubiquitin labeling system of the cell required for normal protein turnover, and its lack prevents NF-κB recycling, resulting in chronic inflammation. A human T cell lymphotropic virus possesses an oncoprotein that subverts this pathway to the virus' benefit by inhibiting A20 interactions with the ubiquitin pathway to promote NF-κB signaling and cell immortalization. The multifunctional A20 protein can act in diverse ways to limit receptor-induced inflammatory signaling. A20 negatively regulates inflammation by inhibiting the nuclear factor κB (NF-κB) 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-κB 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.

Subfields: Cancer Research, Immunology

View Paper: https://www.semanticscholar.org/paper/1e502e16e4e42096ca63e3bb6935978d506dcf76

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Citations in the corpus

Molecular mechanisms of necroptosis: an ordered cellular explosion (2010, background): “It remains unclear whether other deubiquitylating enzymes, including A20 (also known as TNFAIP3”
Signaling in innate immunity and inflammation. (2012, background): “A20 is thought to switch off TLR signaling by countering ubiquitylation by TRAF6 or cIAPs (Newton et al. 2008; Skaug et al. 2009; Shembade et al. 2010).”
The Role of Zinc in Antiviral Immunity (2019, background): “A20 is a regulator of NF-κB- (143), TLR3- (144), and RIGI-mediated (145) IFN production, most likely by targeting PRR signaling components TIRdomain-containing adapter-inducing interferon-β (TRIF), TNF Receptor Associated Factor (TRAF) 2, and TRAF6.”
Inhibiting NF-κB Activation by Small Molecules As a Therapeutic Strategy (2010, positive): “The ubiquitin editing property of A20 was shown to be essential for NF-κB inhibition [100].”
Antioxidant and anti-inflammatory effects of zinc. Zinc-dependent NF-κB signaling (2017, background): “It remains to be determined how A20 collaborate with these proteins, but it is likely that it functions in larger protein complexes modifying ubiquitin-dependent signaling pathways with a high degree of specificity (Shembade et al. 2010; Ma and Malynn 2012).”
The ubiquitin code. (2012, background): “To tribute to this complexity, we focus our discussion on selected roles of ubiquitylation 216 Komander Rape”