The Ubiquitin-Editing Enzyme A20 Restricts Nucleotide-Binding Oligomerization Domain Containing 2-Triggered Signals

Hitotsumatsu, Osamu; Ahmad, Regina Celeste; Tavares, Rita M.; Wang, Min; Philpott, Dana J.; Turer, Emre E.; Lee, Bettina L.; Shiffin, Nataliya; Advincula, Rommel; Malynn, Barbara A.; Werts, Catherine; Ma, Averil

doi:10.1016/j.immuni.2008.02.002

Cited by 295 publications

(262 citation statements)

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“…Coexpression of A20, an enzyme known to counter-regulate Nod2 signaling by deubiquitinating RIP2 (ref. 43), abrogated the Pellino3-mediated ubiquitination of RIP2 (Fig. 5a).…”

Section: Pellino3 Ubiquitinates Rip2mentioning

confidence: 89%

Pellino3 ubiquitinates RIP2 and mediates Nod2-induced signaling and protective effects in colitis

et al. 2013

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The innate immune system is equipped with pattern-recognition receptors that recognize pathogen-associated molecular patterns 1 . Pattern-recognition receptors include transmembrane Toll-like receptors (TLRs) and cytosolic Nod-like receptors 2 . Nod1 and Nod2 recognize structures in bacterial peptidoglycan 3 . Loss-of-function mutants of Nod2 are associated with Crohn's disease 4-6 , whereas gain-offunction mutants result in predisposition to the development of earlyonset sarcoidosis and Blau syndrome 7,8 . Nod2 responds to muramyl dipeptide (MDP), a derivative of peptidoglycan 9,10 . Nod2 consists of two amino-terminal caspase-recruitment domains (CARDs), a central self-oligomerization NACHT region and multiple carboxyterminal leucine-rich repeats 11 . Engagement of the leucine-rich repeats by MDP promotes a conformational change that exposes the NACHT domain, which allows self-oligomerization of Nod2 and the binding of its CARDs to the CARD-containing kinase RIP2 (refs. 12,13). RIP2 interacts with the kinase TAK1, which leads to activation of the transcription factor NF-κB and mitogen-activated protein kinases (MAPKs) and induction of the expression of proinflammatory cytokines [14][15][16][17][18] . Ubiquitination of RIP2 is critical for Nod2 signaling pathways 15,16 .The attachment of polyubiquitin chains to RIP2 serves to recruit TAK1 via the adaptors TAB2 and TAB3 (ref. 19), and that facilitates TAK1-induced phosphorylation and activation of IκB kinases (IKKs) that induce phosphorylation of inhibitory IκB proteins 20 . Phosphorylated IκB proteins undergo proteasome-mediated degradation 21 that allows NF-κB to translocate to the nucleus and induce proinflammatory gene expression 22 . Studies have investigated the enzymes responsible for catalyzing the ubiquitination of RIP2. The Ubc13-Uev1a dimer acts as the E2 conjugating enzyme in the Lys63 (K63)-linked polyubiquitination of RIP2 (refs. 15,16), but the identity of the E3 ubiquitin ligase(s) that directly ubiquitinate(s) RIP2 to mediate Nod2-induced activation of NF-κB remains unclear. TRAF6 has been proposed as the main E3 ligase for RIP2 (ref. 15), but the ubiquitination of RIP2 is intact in TRAF6-deficient cells 16 and knockdown of TRAF6 does not affect RIP2-mediated activation of NF-κB 9,14 . Three members of the 'IAP' family of E3 ubiquitin ligases (XIAP, cIAP1 and cIAP2) have been proposed to regulate RIP2 ubiquitination 23,24 . Although the conclusions of the last two studies differ about the functional importance of cIAP1 and cIAP2 in mediating Nod2-induced ubiquitination of RIP2, one demonstrated that XIAP promotes the ubiquitination of RIP2 and recruitment of the linear ubiquitin chain-assembly complex (LUBAC) to Nod2 (ref. 23). However, the XIAP-mediated polyubiquitination of RIP2 is not K63 linked, a type of linkage associated with RIP2-induced activation of NF-κB. The E3 ligase Itch can also directly ubiquitinate RIP2 to negatively regulate Nod2-induced activation of NF-κB 25 . Thus, it remains unclear which E3 ubiquitin ligase directly cataly...

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“…Coexpression of A20, an enzyme known to counter-regulate Nod2 signaling by deubiquitinating RIP2 (ref. 43), abrogated the Pellino3-mediated ubiquitination of RIP2 (Fig. 5a).…”

Section: Pellino3 Ubiquitinates Rip2mentioning

confidence: 89%

Pellino3 ubiquitinates RIP2 and mediates Nod2-induced signaling and protective effects in colitis

et al. 2013

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“…They recognize peptidoglycan structure of pathogens. Recognition by NLRs induces selfoligomerization of NLRs and actiavates NF-κB and MAPK (Park et al, 2007;Hasegawa et al, 2008;Hitotsumatsu et al, 2008), which subsequently results in the release of IL-1 family of cytokines including IL-1 , IL-18, and IL-33 (Meylan et al, 2006;Fritz et al, 2006;Ting et al, 2006;Kanneganti et al, 2007;Yu & Finlay, 2008). There is feasible evidence supporting that NLRs play a role in the pathogenesis of autoimmune diseases.…”

Section: Pattern Recognitionmentioning

confidence: 99%

Innate Immunity in the Recognition of β-Cell Antigens in Type 1 Diabetes

Zhong¹,

Xu²,

Yang³

et al. 2011

Type 1 Diabetes - Pathogenesis, Genetics and Immunotherapy

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“…In addition to regulating TNF-induced RIP ubiquitylation, A20 restricts TLR-induced NF-B signals by deubiquitylating the E3 ligase TRAF6 (9,11). A20 also dampens NOD1-and NOD2-induced NF-B signals by deubiquitylating RIP2, possibly preventing it from recruiting IKK to the signaling complex (10). Hence, like other DUBs and E3 ligases, A20 regulates the ubiquitylation of multiple protein targets.…”

Section: The Mechanics Of A20 Actionmentioning

confidence: 99%

“…Epistasis experiments revealed that genetic deletion of TNF or TNF receptor 1 (TNFR1) in A20-deficient mice did not rescue the mice from premature death, demonstrating that A20 regulates proinflammatory signals in addition to TNF (9). We now know that A20 also restricts NF-B signaling in response to stimulation of the TLR and NOD pathways (9,10). A20 regulates innate immune homeostasis independently of adaptive immune cells, as A20 / RAG-1 / mice lacking mature T and B cells develop severe spontaneous inflammation and perinatal death (8).…”

mentioning

confidence: 99%