ABINs: A20 binding inhibitors of NF-κB and apoptosis signaling

Verstrepen, Lynn; Carpentier, Isabelle; Verhelst, Kelly; Beyaert, Rudi

doi:10.1016/j.bcp.2009.02.009

Cited by 157 publications

(132 citation statements)

References 76 publications

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“…In resting cells, Cot/tpl-2 forms a stable and inactive complex with p105 NF-kB and ABIN2 (A20-binding inhibitor of NF-kB2), among other proteins, protecting Cot/tpl-2 from degradation. The partial proteolysis of p105 NFkB to p50 NF-kB releases Cot/tpl-2 from the complex [15][16][17][18][19][20]. Dissociated and adequately phosphorylated Cot/tpl2 [21][22][23][24] fully activates MKK1 and consequently Erk1/2, prior to being rapidly degraded through the proteasome pathway [16,17,[25][26][27].…”

Section: Introductionmentioning

confidence: 99%

Cot/tpl2 activity is required for TLR‐induced activation of the Akt p70 S6k pathway in macrophages: Implications for NO synthase 2 expression

et al. 2011

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LPS stimulation activates IKK and different MAP kinase pathways, as well as the PI3K-AktmTOR-p70 S6k pathway, a negative regulator of these MyD88-dependent intracellular signals. Here, we show that Cot/tpl2, a MAP3K responsible for the activation of the MKK1-Erk1/2, controls P-Ser473 Akt and P-Thr389 p70 S6k phosphorylation in LPS-stimulated macrophages. Analysis of the intracellular signalling in Cot/tpl2 KO macrophages versus WT macrophages reveals lower IjBa recovery and higher phosphorylation of JNK and p38a after 1 h of LPS stimulation. Moreover, Cot/tpl2 deficiency increases LPS-induced NO synthase 2 (NOS2) expression in macrophages. Inhibition of the PI3K pathway abolishes the differences in IjBa and NOS2 expression between Cot/tpl2 KO and WT macrophages following LPS administration. Furthermore, in zymosan-and polyI:C-stimulated macrophages, Cot/tpl2 mediates P-Ser473 Akt phosphorylation, increases IjBa levels and decreases NOS2 expression. In conclusion, these data reveal a novel role for the Cot/tpl2 pathway in mediating TLR activation of the Akt-mTOR-p70 S6k pathway, allowing Cot/tpl2 to fine-control the activation state of other signalling pathways.Key words: Akt . Cot/tpl2 . Macrophage . NO synthase 2 . p70 S6k . TLR See accompanying Commentary by Martinez Supporting Information available online IntroductionStimulation of TLRs by the different PAMPs triggers macrophage activation, starting a specific functional program that culminates in the production of inflammatory mediators. With the exception of TLR3, TLRs use MyD88 as a central intracellular adaptor, thereby activating multiple downstream intracellular pathways including IKK. TLR3 and TLR4 recruit the TRIF adaptor, which also activates IKK, but specifically activating TBK1 and the transcription factor IRF3 (reviewed in [1,2]). Translocation of IRF3 to the nucleus is necessary, although not sufficient, to induce IFN-b expression [3]. Most TLRs also activate the PI3K-Akt-mTOR-p70 S6k pathway, which is considered to be a negative regulator of TLR activation in macrophages and myeloid dendritic cells. Inhibition of this PI3K-Akt-mTOR-p70 S6k pathway in TLR-activated cells augments NO synthase 2 (NOS2) expression [4][5][6][7][8].Adequate TLR4 stimulation induces the formation of a TLR receptor complex that recruits proteins such as MyD88 and p85 PI3 K [9]. PI3K subsequently activates the Akt-mTOR-p70 S6k pathway. Moreover, TLR-bound MyD88 recruits IRAK4 and IRAK1. The phosphorylation of IRAK1 by IRAK4 facilitates TRAF6 [1,10]). Activated IKK-b phosphorylates p105 NF-kB at multiple residues [11][12][13], which targets the rapid degradation of p105 NF-kB to p50 NF-kB [11][12][13][14]. In resting cells, Cot/tpl-2 forms a stable and inactive complex with p105 NF-kB and ABIN2 (A20-binding inhibitor of NF-kB2), among other proteins, protecting Cot/tpl-2 from degradation. The partial proteolysis of p105 NFkB to p50 NF-kB releases Cot/tpl-2 from the complex [15][16][17][18][19][20]. Dissociated and adequately phosphorylated Cot/tpl2 [21][22][23][24] fully...

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Section: Introductionmentioning

confidence: 99%

Cot/tpl2 activity is required for TLR‐induced activation of the Akt p70 S6k pathway in macrophages: Implications for NO synthase 2 expression

et al. 2011

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“…In this study, we reveal that A20 recruitment to TbRI-TRAF6 in the presence of TGF-b1 essentially requires Smad6, and subsequently deubiquitinates K63-linked TRAF6 polyubiquitination, resulting in the decrease of TAK1 and p38 MAPK/JNK phosphorylation and AP-1-mediated reporter activity. In certain aspects, this role of Smad6 is likely to be similar to those of ABINs and TAX1BP1, known as A20 adaptors in the inhibition of NF-kB activity in the TNF-a signalling pathway 50,51 . ABINs and TAX1BP1 bind to target substrates such as NEMO and RIP1 through their ubiquitin binding domain (UBD) in the TNF-a pathway and recruit the ubiquitin editing enzyme A20, resulting in the deubiquitination of their K63-linked polyubiquitination 50,51 .…”

Section: Discussionmentioning

confidence: 99%

“…In certain aspects, this role of Smad6 is likely to be similar to those of ABINs and TAX1BP1, known as A20 adaptors in the inhibition of NF-kB activity in the TNF-a signalling pathway 50,51 . ABINs and TAX1BP1 bind to target substrates such as NEMO and RIP1 through their ubiquitin binding domain (UBD) in the TNF-a pathway and recruit the ubiquitin editing enzyme A20, resulting in the deubiquitination of their K63-linked polyubiquitination 50,51 . In particular, ABIN proteins as well as A20 are induced by TNF-a, eventually forming a negative feedback loop of the TNF-a pathway 50 .…”

Section: Discussionmentioning

confidence: 99%

“…ABINs and TAX1BP1 bind to target substrates such as NEMO and RIP1 through their ubiquitin binding domain (UBD) in the TNF-a pathway and recruit the ubiquitin editing enzyme A20, resulting in the deubiquitination of their K63-linked polyubiquitination 50,51 . In particular, ABIN proteins as well as A20 are induced by TNF-a, eventually forming a negative feedback loop of the TNF-a pathway 50 . Therefore, these A20 adaptors, binding to ubiquitinylated targets, determine the specificity of diverse cellular substrates for A20.…”

Section: Discussionmentioning

confidence: 99%

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Smad6 inhibits non-canonical TGF-β1 signalling by recruiting the deubiquitinase A20 to TRAF6

et al. 2013

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Transforming growth factor (TGF)-b, a pivotal cytokine involved in a variety of cellular functions, transmits signals through Smad-dependent canonical and Smad-independent noncanonical pathways. In contrast to the canonical TGF-b pathway, it is unknown how noncanonical TGF-b pathways are negatively regulated. Here we demonstrate that the inhibitory Smad Smad6, but not Smad7, negatively regulates TGF-b1-induced activation of the TRAF6-TAK1-p38 MAPK/JNK pathway, a noncanonical TGF-b pathway. TGF-b1-induced Smad6 abolishes K63-linked polyubiquitination of TRAF6 by recruiting the A20 deubiquitinating enzyme in AML-12 mouse liver cells and primary hepatocytes. In addition, the knockdown of Smad6 or A20 in an animal model or cell culture system maintains TAK1 and p38 MAPK/JNK phosphorylation and increases apoptosis, emphasizing the crucial role of the Smad6-A20 axis in negative regulation of the TGF-b1-TRAF6-TAK1-p38 MAPK/JNK pathway. Therefore, our findings provide insight into the molecular mechanisms underlying negative regulation of noncanonical TGF-b pathways.

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“…Interestingly, although A20 is widely considered as a tumor-suppressor DUB promoting cell death, it also acts as a potent prosurvival gene by inhibiting apoptosis in certain malignancies such as gliomas and breast carcinomas (Vendrell et al, 2007). Moreover, in this regard, A20-binding inhibitors have been described to have a critical role in the inhibition of NF-kB and apoptosis signaling (Verstrepen et al, 2009). Notably, USP20 and USP33 are implicated in Von Hippel-Lindau's syndrome (VHL), a familial cancer syndrome caused by germline mutations of the VHL gene that predispose to various benign and malignant tumors (Li et al, 2002a, b).…”

Section: Other Functional Roles For Dubs In Cancermentioning

confidence: 99%

Deubiquitinases in cancer: new functions and therapeutic options

et al. 2011

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Deubiquitinases (DUBs) have fundamental roles in the ubiquitin system through their ability to specifically deconjugate ubiquitin from targeted proteins. The human genome encodes at least 98 DUBs, which can be grouped into 6 families, reflecting the need for specificity in their function. The activity of these enzymes affects the turnover rate, activation, recycling and localization of multiple proteins, which in turn is essential for cell homeostasis, protein stability and a wide range of signaling pathways. Consistent with this, altered DUB function has been related to several diseases, including cancer. Thus, multiple DUBs have been classified as oncogenes or tumor suppressors because of their regulatory functions on the activity of other proteins involved in tumor development. Therefore, recent studies have focused on pharmacological intervention on DUB activity as a rationale to search for novel anticancer drugs. This strategy may benefit from our current knowledge of the physiological regulatory mechanisms of these enzymes and the fact that growth of several tumors depends on the normal activity of certain DUBs. Further understanding of these processes may provide answers to multiple remaining questions on DUB functions and lead to the development of DUB-targeting strategies to expand the repertoire of molecular therapies against cancer.

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ABINs: A20 binding inhibitors of NF-κB and apoptosis signaling

Cited by 157 publications

References 76 publications

Cot/tpl2 activity is required for TLR‐induced activation of the Akt p70 S6k pathway in macrophages: Implications for NO synthase 2 expression

Cot/tpl2 activity is required for TLR‐induced activation of the Akt p70 S6k pathway in macrophages: Implications for NO synthase 2 expression

Smad6 inhibits non-canonical TGF-β1 signalling by recruiting the deubiquitinase A20 to TRAF6

Deubiquitinases in cancer: new functions and therapeutic options

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