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Organization of MyD88 domains
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MyD88 is the canonical adaptor for inflammatory signaling pathways downstream of members of the Toll-like receptor (TLR) and interleukin-1 (IL-1) receptor families. MyD88 links IL-1 receptor (IL-1R) or TLR family members to IL-1R-associated kinase (IRAK) family kinases via homotypic protein-protein interaction. Activation of IRAK family kinases lea...
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... MyD88 was implicated in signaling down- stream of IL-1R and mammalian TLRs [5][6][7]. The C-terminal TIR (Toll IL-1R) domain mediates the interaction with other TIR domain-containing proteins (receptors or adaptors); the N-terminal death domain (DD) associates with the IRAK family members through homotypic DD interactions ( Figure 1). Consistent with these roles, overexpression of the DD of MyD88 leads to spontaneous activation of NFkB and c-Jun N-terminal kinase (JNK), whereas the TIR domain can act as a dominant negative [5,7,8]. ...
Citations
... MYD88 is involved in signalling in immune cells [18]. It acts as an adapter that connects proteins that receive signals from outside the cell to proteins that relay signals inside the cell and plays an important role in the early immune response to infection [19]. ...
Since 2020, African swine fever (ASF) has affected all pig breeds in Northeast India except Doom pigs, a unique indigenous breed from Assam and the closest relatives of Indian wild pigs. ASF outbreaks result in significant economic losses for pig farmers in the region. Based on sequencing and phylogenetic analysis of the B646L (p72) gene, it has been determined that ASFV genotype II is responsible for outbreaks in this region. Recent studies have shown that MYD88, LDHB, and IFIT1, which are important genes of the immune system, are involved in the pathogenesis of ASFV. The differential expression patterns of these genes in surviving ASFV-infected and healthy Doom breed pigs were compared to healthy controls at different stages of infection. The ability of Doom pigs to withstand common pig diseases, along with their genetic resemblance to wild pigs, make them ideal candidates for studying tolerance to ASFV infection. In the present study, we investigated the natural resistance to ASF in Doom pigs from an endemic area in Northeast India. The results of this study provide important molecular insights into the regulation of ASFV tolerance genes.
... Defensins, a type of small AMP, are specifically produced by insects as part of their innate immune defense and are characterized by their highly conserved cysteine-rich structure, which is essential for their antimicrobial activity [17]. MyD88 serves as a crucial adaptor protein within the Toll pathway, connecting the receptors to downstream signaling pathway components [18][19][20]. The significance of the Toll pathway in combating viruses was first reported in Drosophila infected with Drosophila X virus [21]. ...
... MyD88 is an essential adaptor protein in the Toll pathway, linking the receptors to downstream signaling pathway components [19]. At 6 days padp, SRBSDV infection significantly increased MyD88 transcript level but decreased MyD88 protein expression level, suggesting post-translational degradation of MyD88 (Fig 1D and 1F). ...
... Toll pathways in insects exert strong evolutionary pressure on viruses, and viral evasion of the Toll immune response may occur in a conserved manner [13,23,37]. MyD88, a vital conserved adaptor protein, is considered as a central player in regulating the Toll signaling pathway [19,48,49]. In our study, we discover that the nonstructural protein P7-1 of SRBSDV effectively promotes the E3 ubiquitin ligase SfREL-mediated ubiquitinated degradation of the adaptor protein MyD88 in a proteasome-dependent manner (Fig 8). ...
Many plant arboviruses are persistently transmitted by piercing-sucking insect vectors. However, it remains largely unknown how conserved insect Toll immune response exerts antiviral activity and how plant viruses antagonize it to facilitate persistent viral transmission. Here, we discover that southern rice black-streaked dwarf virus (SRBSDV), a devastating planthopper-transmitted rice reovirus, activates the upstream Toll receptors expression but suppresses the downstream MyD88-Dorsal-defensin cascade, resulting in the attenuation of insect Toll immune response. Toll pathway-induced the small antibacterial peptide defensin directly interacts with viral major outer capsid protein P10 and thus binds to viral particles, finally blocking effective viral infection in planthopper vector. Furthermore, viral tubular protein P7-1 directly interacts with and promotes RING E3 ubiquitin ligase-mediated ubiquitinated degradation of Toll pathway adaptor protein MyD88 through the 26 proteasome pathway, finally suppressing antiviral defensin production. This virus-mediated attenuation of Toll antiviral immune response to express antiviral defensin ensures persistent virus infection without causing evident fitness costs for the insects. E3 ubiquitin ligase also is directly involved in the assembly of virus-induced tubules constructed by P7-1 to facilitate viral spread in planthopper vector, thereby acting as a pro-viral factor. Together, we uncover a previously unknown mechanism used by plant arboviruses to suppress Toll immune response through the ubiquitinated degradation of the conserved adaptor protein MyD88, thereby facilitating the coexistence of arboviruses with their vectors in nature.
... TLR4 is a vital molecule for the initiation of infammatory response and activation of NF-κB, which plays a vital role in cellular activation and production of infammatory cytokines and chemokines [43]. MyD88 functions downstream of TLRs and IL-1 receptor family members and plays a vital role in initiating and propagating signaling pathways, thereby leading to various functional outputs, including the activation of NF-κB and MAPK [44]. Proinfammatory cytokine TNF-α was markedly increased in the DSS group, while anti-infammatory cytokine IL-10 was reduced (Figures 4(a) and 4(b)). ...
Scytosiphon lomentaria is widely consumed in China’s coastal regions due to its various beneficial effects, although its exact mechanism has yet to be fully elucidated. This study demonstrated that S. lomentaria fucoidan (SLF) alleviated colitis symptoms in mice, as evidenced by a reduction in colonic tissue damage and an increase in colon length and weight gain. Metabolomics analysis indicated that SLF improved abnormal serum metabolites profile associated with colitis, affecting metabolic pathways related to amino acid, lipid, and tricarboxylic acid cycle. SLF alleviated colonic inflammation through inhibiting the activation of MAPK/NF-κB pathways and attenuating oxidative stress. The protective effect of SLF in maintaining the gut barrier integrity is supported by the preservation of goblet cells and glycoproteins and increased expression of ZO-1 and claudin. The underlying mechanism can be associated with the improvement of the gut microbiota, including an increase in microbiota diversity and richness and the levels of beneficial bacteria and metabolites (e.g., Muribaculum, Parabacteroides, and short-chain fatty acids) and a reduction in harmful bacteria. This study implies that SLF holds great potential to be used as a prebiotic agent to enhance human and gut health.
... Claudin-1 regulates epithelial homeostasis and its expression downregulation can lead to dysfunctions of the epithelial barrier in these organs [18,19]. MyD88 is a downstream connector of IL-1 and toll-like receptors in the inflammatory signaling pathway [20]. The activation of host innate immunity largely depends on ISSN 2353-5288 Polish Pharmaceutical Society the normal function of MyD88, and dysregulation of its expression will lead to inflammation-related diseases [21]. ...
Atopic dermatitis (AD) is a non-infectious inflammatory skin disease characterized by persistent itching of the skin, and it has become a global health problem with increasing incidence and complex pathogenesis. Momordin Ic (MMI) is a triterpenoid saponin that has anti-inflammatory effect and may play an effective role in the treatment of AD. To explore the molecular mechanism of MMI in relieving AD, and to provide some experimental data for the clinical application of MMI in AD. The mRNA levels of IL-33, IL-4 and NF-κB were detected by RT-qPCR. The protein expressions of Filaggrin, Claudin-1, MyD88 and NLRP3 were detected by western blotting. Transepithelial/transendothelial electrical resistance (TEER) method was used to detect the tight-junction function of HaCaT cells. Molecular docking experiment was performed on CB-DOCK2 to predict the binding of MMI and NLRP3. MMI reversed the decrease of filaggrin protein expression and intercellular resistance in HaCaT cells induced by TNF-α and IFN-γ. In addition, MMI reversed the increase in IL-33 and IL-4 mRNA levels in HaCaT cells treated with TNF-α and IFN-γ. In addition, MMI promoted the expression of Claudin-1 and inhibited the expression of MyD88 and NLRP3. In addition, the molecular docking results showed that MMI and NLRP3 had interaction sites. MMI improved the inflammatory response of HaCaT cells by regulating the expression of Claudin-1/MyD88 and targeting NLRP3, which may act a positive role in relieving AD.
... down-regulated as dietary EPA/DHA ratio decreased from 2.19 to 0.38. These findings showed that, in response to inflammatory stimuli, the up-regulation of nrf2 could occur to inhibit the overproduction of pro-inflammatory cytokines tnf-α in the control group (Deguine and Barton, 2014;Wardyn et al., 2015). ...
... This recognition activates the anti-inflammatory arm of the phosphoinositide 3 kinase (PI3K) pathway, which in turn trains CD4+ Tregs to produce the immunomodulatory cytokine IL-10. Primary response protein 88 (MyD88) of myeloid differentiation functions as an adapter for inflammatory signalling pathways that are downstream of TLR and interleukin-1 (IL-1) receptor family members [80]. Its absence is linked to changed microbiota configuration and a lack of sensitivity to microbial ligands for TLR4 [81]. ...
The gut microbiota affects human health profoundly, and evidence is mounting that it can cause, worsen, or resolve illnesses. Particularly in drug-induced toxicity, its role in diverse toxicological reactions has garnered attention recently. Drugs may interact directly or indirectly, through the gut flora, whether or not they are taken orally, changing the toxicity. Current research focuses mainly on the one-way effect of xenobiotics on the makeup and activities of gut microbes, which leads to altered homeostasis. However, there are two-way interactions between the gut microbiota and xenobiotics, and it is important to consider how the gut microbiota affects xenobiotics, particularly medications. Therefore, we emphasise the microbiome, microbial metabolites, and microbial enzymes in this review to emphasise how the gut microbiota affects medication toxicity. To aid in the identification of micro-biologic targets and processes linked to drug toxicity, we establish connections between medications, the microbiome, microbial enzymes or metabolites, drug metabolites, and host toxicological reactions. In addition, a summary and discussion of contemporary mainstream approaches to control medication toxicity by microbiota targeting are provided.
... The activation of the TLR4/MyD88 signaling pathway through MAPK, ERK1/2, and JNK leads to the regulation of NF-κB and AP-1, thus facilitating upregulation of pro-inflammatory cytokines. [42][43][44]. In the pathogenesis of neuroinflammatory-related diseases, activated astrocytes under inflammatory conditions, through the TLR4/MyD88 signaling pathway, regulate the expression of pro-inflammatory molecules via NF-κB, MAPK, and Jak1/Stat1 pathways, influencing the inflammatory responses of surrounding cells [45,46]. ...
Angiostrongylus cantonensis, a zoonotic parasite, can invade the human central nervous system (CNS) and cause acute eosinophilic meningitis or eosinophilic meningoencephalitis. Mice infected with A. cantonensis show elevated levels of pro-inflammatory cytokines, plasminogen activators, and matrix metalloproteinase-9, resulting in disruption of the blood–brain barrier (BBB) and immune cell infiltration into the CNS. Caveolin-1 (Cav-1) regulates the permeability of the BBB, which affects immune cells and cerebrospinal fluid. This intricate interaction ultimately fuels the progression of brain damage and edema. This study aims to investigate the regulatory role of Cav-1 in the pathogenesis of meningoencephalitis induced by A. cantonensis infection. We investigated pathological alterations by triphenyl-tetrazolium chloride, brain water content, BBB permeability, Western blot analysis, and gelatin zymography in BALB/c mice after A. cantonensis. The study evaluates the critical role of Cav-1 regulation through the TLR4/MyD88 signaling pathway, modulates tight junction proteins, influences BBB permeability, and contributes to brain damage in A. cantonensis-induced meningoencephalitis.
... Glucocorticoids, as metabolic hormones, play a pivotal role in metabolism. During high-intensity anaerobic exercise or prolonged aerobic exercise, there is a significant elevation in the levels of glucocorticoids, especially the main hormone cortisol [125]. Many previous studies have concluded that negative stress and excessive training intensity can lead to the accumulation of cortisol [126]. ...
The diversity and functionality of gut microbiota may play a crucial role in the function of human motor-related systems. In addition to traditional nutritional supplements, there is growing interest in microecologics due to their potential to enhance sports performance and facilitate post-exercise recovery by modulating the gut microecological environment. However, there is a lack of relevant reviews on this topic. This review provides a comprehensive overview of studies investigating the effects of various types of microecologics, such as probiotics, prebiotics, synbiotics, and postbiotics, on enhancing sports performance and facilitating post-exercise recovery by regulating energy metabolism, mitigating oxidative-stress-induced damage, modulating immune responses, and attenuating bone loss. Although further investigations are warranted to elucidate the underlying mechanisms through which microecologics exert their effects. In summary, this study aims to provide scientific evidence for the future development of microecologics in athletics.
... 40 Similarly, MYD88, serving as a central adaptor protein in TLR and IL-1 receptor pathways, has a significant impact on inflammasome activity. 41 It influences the maturation and secretion of inflammatory cytokines, which are crucial in osteosarcoma pathogenesis. The ability of these molecules to modulate the tumour microenvironment suggests they may affect tumour growth, metastasis, and immune escape mechanisms. ...
Osteosarcoma, the primary bone cancer in adolescents and young adults, is notorious for its aggressive growth and metastatic potential. Our study delved into the prognostic impact of inflammasome‐related gene signatures in osteosarcoma patients, employing comprehensive genetic profiling to uncover signatures linked with patient outcomes. We identified three patient subgroups through consensus clustering, with one showing worse survival rates correlated with high FGFR3 and RARB expressions. Immune profiling revealed significant immune cell infiltration differences among these subgroups, affecting survival. Utilising advanced machine learning, including StepCox and gradient boosting machine algorithms, we developed a prognostic model with a notable c‐index of 0.706, highlighting CD36 and MYD88 as key genes. Higher inflammasome risk scores from our model were associated with poorer survival, corroborated across datasets. In vitro experiments validated CD36 and MYD88's roles in promoting osteosarcoma cell proliferation, invasion and migration, emphasising their therapeutic potential. This research offers new insights into inflammasomes' role in osteosarcoma, introducing novel biomarkers for risk assessment and potential therapeutic targets. Our findings suggest a pathway towards personalised treatment strategies, potentially improving patient outcomes in osteosarcoma.
... Myeloid differentiation factor 88 (MyD88), a key intracellular signaling cytoplasmic adaptor protein located on chromosome 3, mediates a variety of toll-like receptors (TLRs), such as interleukin-1 receptor (IL-1R) [1] and interleukin-18 receptor (IL-18R) [2,3]. As an intracellular protein, it connects the TLR family to the IL-1R-associated kinase (IRAK) family through protein-protein interactions [4]. Meanwhile, the activation of IRAK leads to multiple functional outputs, including nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), and protein 1 activation, all of which make MyD88 a critical node in immunomodulation-related pathways [4]. ...
... As an intracellular protein, it connects the TLR family to the IL-1R-associated kinase (IRAK) family through protein-protein interactions [4]. Meanwhile, the activation of IRAK leads to multiple functional outputs, including nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), and protein 1 activation, all of which make MyD88 a critical node in immunomodulation-related pathways [4]. Therefore, the transduction function of this protein has attracted extensive attention. ...
... This suggests that intracellular auto aggregation is possible even if the MyD88 TIR domain is not involved in protein interactions and is located in the DD region of MyD88. However, the N-terminus is not completely useless as it mediates interferon regulatory factor 7 (IRF-7) and promotes the production of type I interferons (IFNs) independent of DD folding [4,18]. Although this intermediate domain does not appear to be directly involved in protein interactions, it is required for activation of IRAK4 [4]. ...
The interplay between the immune system and cancer underscores the central role of immunotherapy in cancer treatment. In this context, the innate immune system plays a critical role in preventing tumor invasion. Myeloid differentiation factor 88 (MyD88) is crucial for innate immunity, and activation of MyD88 promotes the production of inflammatory cytokines and induces infiltration, polarization, and immune escape of immune cells in the tumor microenvironment. Additionally, abnormal MyD88 signaling induces tumor cell proliferation and metastasis, which are closely associated with poor prognosis. Therefore, MyD88 could serve as a novel tumor biomarker and is a promising target for cancer therapy. Current strategies targeting MyD88 including inhibition of signaling pathways and protein multimerization, have made substantial progress, especially in inflammatory diseases and chronic inflammation-induced cancers. However, the specific role of MyD88 in regulating tumor immunity and tumorigenic mechanisms remains unclear. Therefore, this review describes the involvement of MyD88 in tumor immune escape and disease therapy. In addition, classical and non-classical MyD88 inhibitors were collated to provide insights into potential cancer treatment strategies. Despite several challenges and complexities, targeting MyD88 is a promising avenue for improving cancer treatment and has the potential to revolutionize patient outcomes.
