A20 Inhibits LUBAC-mediated NF-κB Activation by Binding Linear Polyubiquitin Chains Via Its Zinc Finger 7

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2012 Oct 4

PMID 23032186

Citations 114

Authors

Kelly Verhelst

Isabelle Carpentier

Marja Kreike

Laura Meloni

Lynn Verstrepen

Tobias Kensche

Ivan Dikic

Rudi Beyaert

Affiliations

Soon will be listed here.

Abstract

Linear polyubiquitination of proteins has recently been implicated in NF-κB signalling and is mediated by the linear ubiquitin chain assembly complex (LUBAC), consisting of HOIL-1, HOIP and Sharpin. However, the mechanisms that regulate linear ubiquitination are still unknown. Here, we show that A20 is rapidly recruited to NEMO and LUBAC upon TNF stimulation and that A20 inhibits LUBAC-induced NF-κB activation via its C-terminal zinc-finger 7 (ZF7) domain. Expression of a polypeptide corresponding to only ZF7 was sufficient to inhibit TNF-induced NF-κB activation. Both A20 and ZF7 can form a complex with NEMO and LUBAC, and are able to prevent the TNF-induced binding of NEMO to LUBAC. Finally, we show that ZF7 preferentially binds linear polyubiquitin chains in vitro, indicating A20-ZF7 as a novel linear ubiquitin-binding domain (LUBID). We thus propose a model in which A20 inhibits TNF- and LUBAC-induced NF-κB signalling by binding to linear polyubiquitin chains via its seventh zinc finger, which prevents the TNF-induced interaction between LUBAC and NEMO.

Citing Articles

A20 as a Potential Therapeutic Target for COVID-19.

Wu Y, He L, Li R, Li J, Zhao Q, Shao B Immun Inflamm Dis. 2025; 13(1):e70127.

PMID: 39853876 PMC: 11760982. DOI: 10.1002/iid3.70127.

A20 intrinsically influences human effector T-cell survival and function by regulating both NF-κB and JNK signaling.

Dabbah-Krancher G, Ruchinskas A, Kallarakal M, Lee K, Bauman B, Epstein B Eur J Immunol. 2024; 54(12):e2451245.

PMID: 39359035 PMC: 11631677. DOI: 10.1002/eji.202451245.

NF-κB regulated expression of A20 controls IKK dependent repression of RIPK1 induced cell death in activated T cells.

Layzell S, Barbarulo A, van Loo G, Beyaert R, Seddon B Cell Death Differ. 2024; 32(2):256-270.

PMID: 39327505 PMC: 11802744. DOI: 10.1038/s41418-024-01383-6.

CARD14 signalosome formation is associated with its endosomal relocation and mTORC1-induced keratinocyte proliferation.

OSullivan P, Aidarova A, Afonina I, Manils J, Thurston T, Instrell R Biochem J. 2024; 481(18):1143-1171.

PMID: 39145956 PMC: 11555713. DOI: 10.1042/BCJ20240058.

Inhibition of NLRP3 inflammasome activation by A20 through modulation of NEK7.

Yu J, Li H, Wu Y, Luo M, Chen S, Shen G Proc Natl Acad Sci U S A. 2024; 121(25):e2316551121.

PMID: 38865260 PMC: 11194493. DOI: 10.1073/pnas.2316551121.

References

Skaug B, Chen J, Du F, He J, Ma A, Chen Z . Direct, noncatalytic mechanism of IKK inhibition by A20. Mol Cell. 2011; 44(4):559-71. PMC: 3237303. DOI: 10.1016/j.molcel.2011.09.015. View

Bosanac I, Wertz I, Pan B, Yu C, Kusam S, Lam C . Ubiquitin binding to A20 ZnF4 is required for modulation of NF-κB signaling. Mol Cell. 2010; 40(4):548-57. DOI: 10.1016/j.molcel.2010.10.009. View

Haas T, Emmerich C, Gerlach B, Schmukle A, Cordier S, Rieser E . Recruitment of the linear ubiquitin chain assembly complex stabilizes the TNF-R1 signaling complex and is required for TNF-mediated gene induction. Mol Cell. 2009; 36(5):831-44. DOI: 10.1016/j.molcel.2009.10.013. View

Chu Y, Vahl J, Kumar D, Heger K, Bertossi A, Wojtowicz E . B cells lacking the tumor suppressor TNFAIP3/A20 display impaired differentiation and hyperactivation and cause inflammation and autoimmunity in aged mice. Blood. 2010; 117(7):2227-36. DOI: 10.1182/blood-2010-09-306019. View

Kensche T, Tokunaga F, Ikeda F, Goto E, Iwai K, Dikic I . Analysis of nuclear factor-κB (NF-κB) essential modulator (NEMO) binding to linear and lysine-linked ubiquitin chains and its role in the activation of NF-κB. J Biol Chem. 2012; 287(28):23626-34. PMC: 3390637. DOI: 10.1074/jbc.M112.347195. View

Wertz I, ORourke K, Zhou H, Eby M, Aravind L, Seshagiri S . De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling. Nature. 2004; 430(7000):694-9. DOI: 10.1038/nature02794. View

Schmitz R, Hansmann M, Bohle V, Martin-Subero J, Hartmann S, Mechtersheimer G . TNFAIP3 (A20) is a tumor suppressor gene in Hodgkin lymphoma and primary mediastinal B cell lymphoma. J Exp Med. 2009; 206(5):981-9. PMC: 2715030. DOI: 10.1084/jem.20090528. View

Iha H, Peloponese J, Verstrepen L, Zapart G, Ikeda F, Smith C . Inflammatory cardiac valvulitis in TAX1BP1-deficient mice through selective NF-kappaB activation. EMBO J. 2008; 27(4):629-41. PMC: 2262037. DOI: 10.1038/emboj.2008.5. View

Hammer G, Turer E, Taylor K, Fang C, Advincula R, Oshima S . Expression of A20 by dendritic cells preserves immune homeostasis and prevents colitis and spondyloarthritis. Nat Immunol. 2011; 12(12):1184-93. PMC: 3419270. DOI: 10.1038/ni.2135. View

10.

Sato Y, Fujita H, Yoshikawa A, Yamashita M, Yamagata A, Kaiser S . Specific recognition of linear ubiquitin chains by the Npl4 zinc finger (NZF) domain of the HOIL-1L subunit of the linear ubiquitin chain assembly complex. Proc Natl Acad Sci U S A. 2011; 108(51):20520-5. PMC: 3251058. DOI: 10.1073/pnas.1109088108. View

11.

Verstrepen L, Verhelst K, Carpentier I, Beyaert R . TAX1BP1, a ubiquitin-binding adaptor protein in innate immunity and beyond. Trends Biochem Sci. 2011; 36(7):347-54. DOI: 10.1016/j.tibs.2011.03.004. View

12.

Boone D, Turer E, Lee E, Ahmad R, Wheeler M, Tsui C . The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses. Nat Immunol. 2004; 5(10):1052-60. DOI: 10.1038/ni1110. View

13.

Coornaert B, Carpentier I, Beyaert R . A20: central gatekeeper in inflammation and immunity. J Biol Chem. 2008; 284(13):8217-21. PMC: 2659177. DOI: 10.1074/jbc.R800032200. View

14.

Verstrepen L, Carpentier I, Verhelst K, Beyaert R . ABINs: A20 binding inhibitors of NF-kappa B and apoptosis signaling. Biochem Pharmacol. 2009; 78(2):105-14. DOI: 10.1016/j.bcp.2009.02.009. View

15.

Gerlach B, Cordier S, Schmukle A, Emmerich C, Rieser E, Haas T . Linear ubiquitination prevents inflammation and regulates immune signalling. Nature. 2011; 471(7340):591-6. DOI: 10.1038/nature09816. View

16.

Xu M, Skaug B, Zeng W, Chen Z . A ubiquitin replacement strategy in human cells reveals distinct mechanisms of IKK activation by TNFalpha and IL-1beta. Mol Cell. 2009; 36(2):302-14. PMC: 2779160. DOI: 10.1016/j.molcel.2009.10.002. View

17.

Tokunaga F, Nakagawa T, Nakahara M, Saeki Y, Taniguchi M, Sakata S . SHARPIN is a component of the NF-κB-activating linear ubiquitin chain assembly complex. Nature. 2011; 471(7340):633-6. DOI: 10.1038/nature09815. View

18.

Li L, Soetandyo N, Wang Q, Ye Y . The zinc finger protein A20 targets TRAF2 to the lysosomes for degradation. Biochim Biophys Acta. 2008; 1793(2):346-53. PMC: 2657479. DOI: 10.1016/j.bbamcr.2008.09.013. View

19.

Grabbe C, Husnjak K, Dikic I . The spatial and temporal organization of ubiquitin networks. Nat Rev Mol Cell Biol. 2011; 12(5):295-307. PMC: 3654194. DOI: 10.1038/nrm3099. View

20.

Vereecke L, Sze M, Mc Guire C, Rogiers B, Chu Y, Schmidt-Supprian M . Enterocyte-specific A20 deficiency sensitizes to tumor necrosis factor-induced toxicity and experimental colitis. J Exp Med. 2010; 207(7):1513-23. PMC: 2901067. DOI: 10.1084/jem.20092474. View