The ubiquitin ligase Peli1 negatively regulates T cell activation and prevents autoimmunity

Chang, Mikyoung; Jin, Wei; Chang, Jae Hoon; Xiao, Yichuan; Brittain, George C.; Yu, Jiayi; Zhou, Xiaofei; Wang, Yi Hong; Cheng, Xuhong; Li, Pingwei; Rabinovich, Brian A.; Hwu, Patrick; Sun, Shao Cong

doi:10.1038/ni.2090

Cited by 171 publications

(250 citation statements)

References 51 publications

(88 reference statements)

Supporting

Mentioning

247

Contrasting

Order By: Relevance

“…While most studies to date have focused on Pellino proteins as regulators of IL-1 and TLR signalling, the present report extends their roles beyond these pathways. Furthermore, Peli1 has been described as an important regulator of T-cell activation and self tolerance 52,60 . Such findings, in conjunction with the present report, add to an increasing appreciation of the importance of the Pellino family in a variety of signalling pathways in the innate and adaptive immune systems.…”

Section: Discussionmentioning

confidence: 99%

Pellino3 targets RIP1 and regulates the pro-apoptotic effects of TNF-α

et al. 2013

View full text Add to dashboard Cite

Tumour necrosis factor-a (TNF) can activate NF-kB to induce pro-inflammatory genes but can also stimulate the caspase cascade to promote apoptosis. Here we show that deficiency of the ubiquitin E3 ligase, Pellino3, sensitizes cells to TNF-induced apoptosis without inhibiting the NF-kB pathway. Suppressed expression of Pellino3 leads to enhanced formation of the death-induced signalling complex, complex II, in response to TNF. We show that Pellino3 targets RIP1, in a TNF-dependent manner, to inhibit TNF-induced complex II formation and caspase 8-mediated cleavage of RIP1 in response to TNF/cycloheximide co-stimulation. Pellino3-deficient mice also show increased sensitivity to TNF-induced apoptosis and greatly increased lethality in response to TNF administration. These findings define Pellino3 as a novel regulator of TNF signalling and an important determining factor in dictating whether TNF induces cell survival or death.

show abstract

Section: Discussionmentioning

confidence: 99%

Pellino3 targets RIP1 and regulates the pro-apoptotic effects of TNF-α

et al. 2013

View full text Add to dashboard Cite

show abstract

“…Pellino proteins undergo 9 2 8 VOLUME 14 NUMBER 9 SEPTEMBER 2013 nature immunology A r t i c l e s phosphorylation that regulates their E3 ligase activity [31][32][33][34][35] . Pellino1 is a key mediator of NF-κB activation in the TLR3 and TLR4 signaling pathways 36 and is a negative regulator of T cell activation 37,38 . Pellino3 negatively regulates the TLR3-induced expression of type I interferons 39 .…”

mentioning

confidence: 99%

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

et al. 2013

View full text Add to dashboard Cite

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...

show abstract

“…12 It is thus likely that Peli1 is a target gene of IRF3. Since Peli1 is also induced in T cells by the TCR and CD28 costimulatory signals, 10 it raises the question of which signaling pathway and transcription factor mediates the T cell-specific Peli1 induction. The induction of Peli1 in T cells appears to serve as an autoregulatory mechanism to prevent aberrant NF-kB activation and T-cell activation.…”

Section: Transcriptional Regulationmentioning

confidence: 99%

“…7,8 Recent gene targeting studies have provided new insights into the in vivo biological functions of Peli. 9,10 Important progress has also been made to elucidate the biochemical mechanism mediating signal-induced Peli activation. [11][12][13] In this review, we discuss the recent progress on the regulation and biological functions of Peli in the context of immune receptor signaling and inflammation.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Peli: a family of signal-responsive E3 ubiquitin ligases mediating TLR signaling and T-cell tolerance

2012

Self Cite

View full text Add to dashboard Cite

E3 ubiquitin ligases play a crucial role in regulating immune receptor signaling and modulating immune homeostasis and activation. One emerging family of such E3s is the Pelle-interacting (Peli) proteins, characterized by the presence of a cryptic forkhead-associated domain involved in substrate binding and an atypical RING domain mediating formation of both lysine (K) 63-and K48-linked polyubiquitin chains. A well-recognized function of Peli family members is participation in the signal transduction mediated by Toll-like receptors (TLRs) and IL-1 receptor. Recent gene targeting studies have provided important insights into the in vivo functions of Peli1 in the regulation of TLR signaling and inflammation. These studies have also extended the biological functions of Peli1 to the regulation of T-cell tolerance. Consistent with its immunoregulatory functions, Peli1 responds to different immune stimuli for its gene expression and catalytic activation. In this review, we discuss the recent progress, as well as the historical perspectives in the regulation and biological functions of Peli.

show abstract

The ubiquitin ligase Peli1 negatively regulates T cell activation and prevents autoimmunity

Cited by 171 publications

References 51 publications

Pellino3 targets RIP1 and regulates the pro-apoptotic effects of TNF-α

Pellino3 targets RIP1 and regulates the pro-apoptotic effects of TNF-α

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

Peli: a family of signal-responsive E3 ubiquitin ligases mediating TLR signaling and T-cell tolerance

Contact Info

Product

Resources

About