Homeostatic MyD88-dependent signals cause lethal inflamMation in the absence of A20

Turer, Emre E.; Tavares, Rita M.; Mortier, Erwan; Hitotsumatsu, Osamu; Advincula, Rommel; Lee, Bettina; Shifrin, Nataliya; Malynn, Barbara A.; Ma, Averil

doi:10.1084/jem.20071108

Cited by 250 publications

(247 citation statements)

References 45 publications

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“…However, the cachexia and wasting in A20-deficient mice could not be fully attributed to overactivation of TNF signaling because a multi-inflammatory phenotype and premature death were also observed in double A20/TNF-deficient mice. Bone marrow transfer of A20-deficient hematopoietic cells into a wild-type background gives a similar phenotype as the total knock-out, whereas absence of lymphocytes in double A20/RAG1-deficient mice does not ameliorate the phenotype (7,8). These findings suggest a crucial role for macrophages in the phenotype of A20 knock-out mice.…”

Section: Inhibitory Effect Of A20 On Pro-inflammatory Gene Expressionmentioning

confidence: 86%

A20: Central Gatekeeper in Inflammation and Immunity

Coornaert

Carpentier

Beyaert

2009

Journal of Biological Chemistry

291

253

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Inappropriate functioning of the immune system is linked to immune deficiency, autoimmune disease, and cancer. It is therefore not surprising that intracellular immune signaling pathways are tightly controlled. One of the best studied transcription factors in immune signaling is NF-B, which is activated by multiple receptors and regulates the expression of a wide variety of proteins that control innate and adaptive immunity. A20 is an early NF-B-responsive gene that encodes a ubiquitin-editing protein that is involved in the negative feedback regulation of NF-B signaling. Here, we discuss the mechanism of action of A20 and its role in the regulation of inflammation and immunity. A20 (also known as TNFAIP3) was originally identified as a TNF 2 -inducible gene in human umbilical vein endothelial cells (1). Subsequent research demonstrated that A20 is also induced in many other cell types and by a wide range of other stimuli (reviewed in Ref. 2). Although A20 was originally characterized as an inhibitor of TNF-induced apoptosis (3), it has been most intensively studied as an inhibitor of NF-B activation. NF-B is a dimeric transcription factor that plays a key role in inflammation and immunity. A deregulated NF-B response has been associated with several autoimmune diseases and some cancers (4). The activity of NF-B is tightly regulated by interaction with inhibitory IB (inhibitor of B) proteins, which are regulated by IKK-mediated IB phosphorylation, followed by their ubiquitination and proteolysis, enabling the entry of NF-B into the nucleus. In most cases, the activation of NF-B is transient and cyclic upon continuous stimulation, which is due to specific negative feedback control systems such as the NF-Binducible synthesis of IB and A20 proteins (5). NF-B activation pathways are broadly classified as either canonical or noncanonical, depending on whether activation involves IB degradation or processing of the p100 NF-B precursor (4).The canonical pathway, which is the predominant NF-B signaling pathway, is activated by pro-inflammatory cytokines such as TNF and IL-1 and microbial components that activate, for example, TLRs or antigen receptors. The non-canonical pathway of NF-B activation operates mainly in B cells in response to a subset of TNFR family members, including the lymphotoxin-␤ receptor.Initial evidence for the NF-B inhibitory function of A20 came from several studies in which overexpression of A20 was shown to prevent NF-B activation in response to TNF and several other pro-inflammatory stimuli (reviewed in Ref.2). The observation that A20 expression is itself under the control of NF-B suggested its involvement in the negative feedback regulation of NF-B activation (6). This was eventually confirmed by the generation of A20-deficient mice, which show a sustained NF-B response and severe inflammation (7). The mechanism by which A20 inhibits NF-B activation remained a mystery for several years until it was recently found that A20 can act as a dual ubiquitin-editing enzyme.

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Section: Inhibitory Effect Of A20 On Pro-inflammatory Gene Expressionmentioning

confidence: 86%

A20: Central Gatekeeper in Inflammation and Immunity

Coornaert

Carpentier

Beyaert

2009

Journal of Biological Chemistry

291

253

View full text Add to dashboard Cite

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“…Mice genetically deficient for A20 develop severe systemic inflammation, cachexia, and succumb to an early death, a process alleviated in the absence of MyD88 or upon deletion of the intestinal flora with broad-spectrum antibiotics (11). Another TLR regulator, SIGIRR, regulates intestinal inflammation and susceptibility to DSSinduced colitis (40), as well as regulating susceptibility to lupus (41).…”

Section: Discussionmentioning

confidence: 99%

Role for B-cell adapter for PI3K (BCAP) as a signaling adapter linking Toll-like receptors (TLRs) to serine/threonine kinases PI3K/Akt

Troutman

Fulenchek

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

163

180

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Toll like receptors (TLRs) use Toll-IL-1 receptor (TIR) domain-containing adapters, such as myeloid differentiation primary response gene 88 (MyD88) and TIR domain-containing adapter inducing IFN-β (TRIF), to induce activation of transcription factors, including NF-κB, MAP kinases, and IFN regulatory factors. TLR signaling also leads to activation of PI3K, but the molecular mechanism is not understood. Here we have discovered a unique role for B-cell adapter for PI3K (BCAP) in the TLR-signaling pathway. We find that BCAP has a functional N-terminal TIR homology domain and links TLR signaling to activation of PI3K. In addition, BCAP negatively regulates proinflammatory cytokine secretion upon TLR stimulation. In vivo, the absence of BCAP leads to exaggerated recruitment of inflammatory myeloid cells following infections and enhanced susceptibility to dextran sulfate sodium-induced colitis. Our results demonstrate that BCAP is a unique TIR domaincontaining TLR signaling adapter crucial for linking TLRs to PI3K activation and regulating the inflammatory response.inflammation | negative regulator | macrophage | innate immunity | pattern recognition receptors

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“…Several negative regulators of TLR signaling, including IRAK3 (also known as IRAKM), SIGIRR and A20, to name just a few, have been previously identified and described. [25][26][27][28] In addition, many studies implicate phosphoinositide 3-kinases (PI3K) and its substrate AKT in regulation of TLR signaling. [5][6][7]29,30 The PI3K pathway integrally regulates important cellular processes, including cell survival and proliferation.…”

Section: Introductionmentioning

confidence: 99%