Toll-like receptors, signaling adapters and regulation of the pro-inflammatory response by PI3K

Troutman, Ty Dale; Bazán, J. Fernando; Pasare, Chandrashekhar

doi:10.4161/cc.21572

Cited by 175 publications

(135 citation statements)

References 97 publications

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“…[20][21][22] In the PI3K pathway, the extracellular signals indirectly activate the PI3Ks: phosphatidylinositol 3-kinase, regulatory subunit, polypeptide 2 (Pik3r2) and Pik3r1. The PI3Ks promote the synthesis of PI(3,4,5)P3 (phosphatidylinositol (3,4,5)-trisphosphate), which further activates the protein kinase B (Pkb or AKT).…”

Section: Discussionmentioning

confidence: 99%

Maternal factors required for oocyte developmental competence in mice: Transcriptome analysis of non-surrounded nucleolus (NSN) and surrounded nucleolus (SN) oocytes

Luo

et al. 2013

Cell Cycle

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Section: Discussionmentioning

confidence: 99%

Maternal factors required for oocyte developmental competence in mice: Transcriptome analysis of non-surrounded nucleolus (NSN) and surrounded nucleolus (SN) oocytes

Luo

et al. 2013

Cell Cycle

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“…However, note that there are conflicting results describing TLR-induced PI3K activity as either a positive or negative regulator of macrophage cytokine production. Varying protocols utilizing the pan-PI3K inhibitors, LY294002 and wortmannin, as well as yet to be identified functions of regulators of the PI3K signaling cascade might account for some of these differences (68).…”

Section: Discussionmentioning

confidence: 99%

RP105 Engages Phosphatidylinositol 3-Kinase p110δ To Facilitate the Trafficking and Secretion of Cytokines in Macrophages during Mycobacterial Infection

Micaroni

Puyskens

et al. 2015

The Journal of Immunology

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Cytokines are key regulators of adequate immune responses to infection with Mycobacterium tuberculosis. We demonstrate that the p110δ catalytic subunit of PI3K acts as a downstream effector of the TLR family member RP105 (CD180) in promoting mycobacteria-induced cytokine production by macrophages. Our data show that the significantly reduced release of TNF and IL-6 by RP105−/− macrophages during mycobacterial infection was not accompanied by diminished mRNA or protein expression. Mycobacteria induced comparable activation of NF-κB and p38 MAPK signaling in wild-type (WT) and RP105−/− macrophages. In contrast, mycobacteria-induced phosphorylation of Akt was abrogated in RP105−/− macrophages. The p110δ-specific inhibitor, Cal-101, and small interfering RNA–mediated knockdown of p110δ diminished mycobacteria-induced TNF secretion by WT but not RP105−/− macrophages. Such interference with p110δ activity led to reduced surface-expressed TNF in WT but not RP105−/− macrophages, while leaving TNF mRNA and protein expression unaffected. Activity of Bruton’s tyrosine kinase was required for RP105-mediated activation of Akt phosphorylation and TNF release by mycobacteria-infected macrophages. These data unveil a novel innate immune signaling axis that orchestrates key cytokine responses of macrophages and provide molecular insight into the functions of RP105 as an innate immune receptor for mycobacteria.

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“…BCAP recruitment and the resulting PI3K activation serve as a checkpoint to limit TLR-induced inflammation (5). BCAP represses MyD88-dependent NF-kB and MAPK activation and there might be two different scenarios for this: in the first, BCAP interferes with the TIR domain signalosome (6,31). In the second, BCAP may allow signalosome formation and function downstream of MyD88 but still interfere with the conventional downstream NF-kB pathway; because Akt is not activated in the absence of MyD88 in macrophages (6) and MyD88 is vital for the recruitment of PI3K p85 regulatory subunit (30).…”

Section: Bcapmentioning

confidence: 99%

A Structural View of Negative Regulation of the Toll-like Receptor-Mediated Inflammatory Pathway

Guven-Maiorov

Keskin

Gürsoy

et al. 2015

Biophysical Journal

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Even though the Toll-like receptor (TLR) pathway is integral to inflammatory defense mechanisms, its excessive signaling may be devastating. Cells have acquired a cascade of strategies to regulate TLR signaling by targeting protein-protein interactions, or ubiquitin chains, but the details of the inhibition mechanisms are still unclear. Here, we provide the structural basis for the regulation of TLR signaling by constructing architectures of protein-protein interactions. Structural data suggest that 1) Toll/IL-1R (TIR) domain-containing regulators (BCAP, SIGIRR, and ST2) interfere with TIR domain signalosome formation; 2) major deubiquitinases such as A20, CYLD, and DUBA prevent association of TRAF6 and TRAF3 with their partners, in addition to removing K63-linked ubiquitin chains that serve as a docking platform for downstream effectors; 3) alternative downstream pathways of TLRs also restrict signaling by competing to bind common partners through shared binding sites. We also performed in silico mutagenesis analysis to characterize the effects of oncogenic mutations on the negative regulators and to observe the cellular outcome (whether there is/is not inflammation). Missense mutations that fall on interfaces and nonsense/frameshift mutations that result in truncated negative regulators disrupt the interactions with the targets, thereby enabling constitutive activation of the nuclear factor-kappa B, and contributing to chronic inflammation, autoimmune diseases, and oncogenesis.

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Toll-like receptors, signaling adapters and regulation of the pro-inflammatory response by PI3K

Cited by 175 publications

References 97 publications

Maternal factors required for oocyte developmental competence in mice: Transcriptome analysis of non-surrounded nucleolus (NSN) and surrounded nucleolus (SN) oocytes

Maternal factors required for oocyte developmental competence in mice: Transcriptome analysis of non-surrounded nucleolus (NSN) and surrounded nucleolus (SN) oocytes

RP105 Engages Phosphatidylinositol 3-Kinase p110δ To Facilitate the Trafficking and Secretion of Cytokines in Macrophages during Mycobacterial Infection

A Structural View of Negative Regulation of the Toll-like Receptor-Mediated Inflammatory Pathway

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