Dataset Information

Data-Driven Modeling Identifies TIRAP-Independent MyD88 Activation Complex and Myddosome Assembly Strategy in LPS/TLR4 Signaling.

ABSTRACT: TLR4 complexes are essential for the initiation of the LPS-induced innate immune response. The Myddosome, which mainly contains TLR4, TIRAP, MyD88, IRAK1/4 and TRAF6 proteins, is regarded as a major complex of TLR4. Although the Myddosome has been well studied, a quantitative description of the Myddosome assembly dynamics is still lacking. Furthermore, whether some unknown TLR4 complexes exist remains unclear. In this study, we constructed a SWATH-MS data-based mathematical model that describes the component assembly dynamics of TLR4 complexes. In addition to Myddosome, we suggest that a TIRAP-independent MyD88 activation complex is formed upon LPS stimulation, in which TRAF6 is not included. Furthermore, quantitative analysis reveals that the distribution of components in TIRAP-dependent and -independent MyD88 activation complexes are LPS stimulation-dependent. The two complexes compete for recruiting IRAK1/4 proteins. MyD88 forms higher-order assembly in the Myddosome and we show that the strategy to form higher-order assembly is also LPS stimulation-dependent. MyD88 forms a long chain upon weak stimulation, but forms a short chain upon strong stimulation. Higher-order assembly of MyD88 is directly determined by the level of TIRAP in the Myddosome, providing a formation mechanism for efficient signaling transduction. Taken together, our study provides an enhanced understanding of component assembly dynamics and strategies in TLR4 complexes.

SUBMITTER: Li X

PROVIDER: S-EPMC7246728 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Data-Driven Modeling Identifies TIRAP-Independent MyD88 Activation Complex and Myddosome Assembly Strategy in LPS/TLR4 Signaling.

Li Xiang X Zhong Chuan-Qi CQ Yin Zhiyong Z Qi Hong H Xu Fei F He Qingzu Q Shuai Jianwei J

International journal of molecular sciences 20200426 9

TLR4 complexes are essential for the initiation of the LPS-induced innate immune response. The Myddosome, which mainly contains TLR4, TIRAP, MyD88, IRAK1/4 and TRAF6 proteins, is regarded as a major complex of TLR4. Although the Myddosome has been well studied, a quantitative description of the Myddosome assembly dynamics is still lacking. Furthermore, whether some unknown TLR4 complexes exist remains unclear. In this study, we constructed a SWATH-MS data-based mathematical model that describes ...[more]

PMID: 32357531

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Project description:Diffuse large B‑cell lymphoma (DLBCL), the most common type of non‑Hodgkin's lymphoma, is classified into germinal center and activated B cell (ABC) subtypes. The myeloid differentiation primary response gene 88 (MYD88) L265P mutation is the most prevalent oncogenic mutation among patients with ABC DLBCL, the subtype that has the more inferior outcome. MYD88 oligomerization driven by the L265P mutant augments myddosome assembly and triggers the activation of nuclear factor kappa‑light‑chain‑enhancer of activated B cells (NF‑κB) signaling, highlighting MYD88 oligomerization as a potential therapeutic target for this malignancy. The synthetic peptidomimetic compound ST2825, which has previously been used as an anti‑inflammatory agent, has been reported to inhibit MYD88 dimerization. In the present study, the anticancer effects of ST2825 were investigated using L265P‑expressing ABC DLBCL cell lines. Using confocal microscopy and high‑molecular‑weight fraction experiments, it was revealed that L265P‑associated myddosome assembly was disrupted by ST2825. The results also revealed that disrupting myddosome assembly promoted the death of ABC DLBCL cells harboring the L265P mutation, as well as downregulating survival signals, including the inhibition of NF‑κB and the suppression of IL‑10 and interferon‑β production. Further co‑immunoprecipitation studies demonstrated that MYD88 bound to BTK in L265P‑DLBCL cells, and that this binding was abrogated following ST2825 treatment. Furthermore, the combination of myddosome‑assembly disruption and BTK or BCL‑2 signaling inhibition led to synergistic ABC DLBCL cell death, and more robust inhibition of NF‑κB activity or increased apoptosis, respectively. The results of the present study provide evidence that the synthetic peptidomimetic compound ST2825, which targets myddosome assembly, may serve as a pharmacological inhibitor. ST2825 has the potential for clinical use in patients with L265P DLBCL, and other B‑cell neoplasms driven by activated MYD88 signaling.

Dataset Information

Data-Driven Modeling Identifies TIRAP-Independent MyD88 Activation Complex and Myddosome Assembly Strategy in LPS/TLR4 Signaling.

Publications

Data-Driven Modeling Identifies TIRAP-Independent MyD88 Activation Complex and Myddosome Assembly Strategy in LPS/TLR4 Signaling.

Similar Datasets

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