MyD88: A Critical Adaptor Protein in Innate Immunity Signal Transduction

Warner, Neil; Núñez, Gabriel

doi:10.4049/jimmunol.1203103

Cited by 148 publications

(127 citation statements)

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“…After TLR4 was discovered as the receptor for LPS, another cell surface protein, MD-2, was shown to also interact with TLR4 during LPS signaling (13). Crystal structures further demonstrated, using LPS (14) and Eritoran, an analog of LPS (15), that TLR4 and MD-2 dimerized with the Lipid A component of LPS and then, like other members of the IL-1/IL-18/Toll receptor superfamily, induced NF-kB through the signal adaptor protein MyD88, which was featured previously in Pillars of Immunology (16).…”

Section: Tlr4: the Winding Road To The Discovery Of The Lps Receptorsupporting

confidence: 53%

TLR4: The Winding Road to the Discovery of the LPS Receptor

Murdock

Núñez

2016

The Journal of Immunology

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Section: Tlr4: the Winding Road To The Discovery Of The Lps Receptorsupporting

confidence: 53%

TLR4: The Winding Road to the Discovery of the LPS Receptor

Murdock

Núñez

2016

The Journal of Immunology

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“…This means that the antibacterial VSIG4 signal also requires MYD88, the adapter protein for PAMP receptors. 43 Indeed, LM infection itself stimulated conversion of LC3B-I to LC3B-II in HeLa-mock and HeLa-HsVSIG4 cells, and this was further enhanced by treating with anti-HsVSIG4 mAb (Fig. 5C).…”

Section: Discussionmentioning

confidence: 86%

Extracellular stimulation of VSIG4/complement receptor Ig suppresses intracellular bacterial infection by inducing autophagy

et al. 2016

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VSIG4/CRIg (V-set and immunoglobulin domain containing 4) is a transmembrane receptor of the immunoglobulin superfamily that is expressed specifically on macrophages and mature dendritic cells. VSIG4 signaling accelerates phagocytosis of C3-opsonized bacteria, thereby efficiently clearing pathogens within macrophages. We found that VSIG4 signaling triggered by C3-opsonized Listeria (opLM) or by agonistic anti-VSIG4 monoclonal antibody (mAb) induced macrophages to form autophagosomes. VSIG4-induced autophagosomes were selectively colocalized with the intracellular LM while starvation-induced autophagosomes were not. Consistent with these results, the frequency of autophagosomes induced by infection with opLM was lower in VSIG4-deficient bone marrow-derived macrophages (BMDMs) than in WT BMDMs. Furthermore, when VSIG4 molecules were overexpressed in HeLa cells, which are nonmacrophage cells, VSIG4 triggering led to efficient uptake of LM, autophagosome formation, and killing of the infected LM. These findings suggest that VSIG4 signaling not only promotes rapid phagocytosis and killing of C3-opsonized intracellular bacteria, as previously reported, but also induces autophagosome formation, eliminating the LM that have escaped from phagosomes. We conclude that VSIG4 signaling provides an anti-immune evasion mechanism that prevents the outgrowth of intracellular bacteria in macrophages.

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“…MYD88 is an adaptor molecule that plays a critical role in mediating signaling responses induced by activation of IL-1/ IL-18/Toll receptor superfamily members by coupling these receptors to the IRAK complex to induce activation of NF-κB and ERK-MAP kinase, leading to the release of proinflammatory cytokines (8,37,38). Notably, we found a substantial increase in keratinocyte-intrinsic MYD88 protein expression in the skin of Rabgef1 K-KO mice ( Figure 4, D and E), suggesting that MYD88 may play an important role in RABGEF1-dependent signaling in keratinocytes.…”

Section: Resultsmentioning

confidence: 99%

“…Supporting this, gene set enrichment analysis (GSEA), used to compare the transcriptome of Rabgef1 K-KO and control skin with defined gene sets, revealed a significant enrichment, among genes upregulated in Rabgef1 K-KO skin samples, of genes implicated in the cell cycle or regulated by NF-κB ( Figure 5). In addition, there was a significant enrichment, among genes upregulated in control skin samples, of genes involved in barrier function ( Figure 5), further supporting the conclusion that epidermal barrier function is impaired when RABGEF1 is absent.MYD88 is an adaptor molecule that plays a critical role in mediating signaling responses induced by activation of IL-1/ IL-18/Toll receptor superfamily members by coupling these receptors to the IRAK complex to induce activation of NF-κB and ERK-MAP kinase, leading to the release of proinflammatory cytokines (8,37,38). Notably, we found a substantial increase in keratinocyte-intrinsic MYD88 protein expression in the skin of Rabgef1 D and E), suggesting that MYD88 may play an important role in RABGEF1-dependent signaling in keratinocytes.…”

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confidence: 99%

Guanine nucleotide exchange factor RABGEF1 regulates keratinocyte-intrinsic signaling to maintain skin homeostasis

Marichal¹,

Gaudenzio²,

Abbas³

et al. 2016

Journal of Clinical Investigation

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, 2-way ANOVA with Bonferroni's test for multiple comparisons (G and K), or Mann-Whitney test (L). *P < 0.05; **P < 0.01; ***P < 0.001. Scale bars: 50 μm; original magnification in B and I, ×20; NS, not significant. The Journal of Clinical Investigation R E S E A R C H A R T I C L E4 4 9 9 jci.org Volume 126 Number 12 December 2016 some expression of keratin 14 (K14) in epithelial cells. However, these organs did not exhibit histological abnormalities (Supplemental Figure 3). These results indicate that the cause of death in such mice is more likely related to the skin abnormalities. Because of the accelerated mortality in Rabgef1 K-KO mice, and to assess the function of keratinocyte-intrinsic RABGEF1 in adult mice that would exhibit no potential developmental effects of constitutive Rabgef1 deletion, we generated mice in which Rabgef1 can be depleted in keratinocytes by tamoxifen treatment, i.e., K14-Cre-ERT2 + Rabgef1 fl/fl mice (called Rabgef1 KERT2-KO mice). Topical tamoxifen treatment on the back skin of adult Rabgef1 KERT2-KO mice, but not adult Rabgef1 fl/fl mice, promoted the development of skin lesions that were similar to those in Rabgef1 K-KO mice and were associated with RABGEF1 deletion in keratinocytes (Figure 1, H-K). Such skin lesions were associated with a modest, albeit statistically significant, increase in the number of bacteria that could be cultured from the affected skin ( Figure 1L), but not with evidence of associated systemic bacterial infection (Supplemental Figure 4).RABGEF1 deletion in keratinocytes results in epidermal barrier dysfunction, features of type 2 skin inflammation, and elevated levels of IgE antibodies. Histological and immunohistological analyses of back skin from newborn mice did not reveal obvious differences between Rabgef1 K-KO and control mice (Supplemental Figure 5). By contrast, back skin lesions of postnatal day 7-9 as well as day 49-56 (i.e., adult) Rabgef1 K-KO mice exhibited marked epidermal hyperplasia (Figure 1, F and G) and spongiosis ( Figure 2A These observations prompted us to investigate whether keratinocyte-intrinsic RABGEF1 deficiency resulted in epidermal barrier dysfunction. We used our model of inducible keratinocyte Rabgef1 deletion by topical tamoxifen treatment of Rabgef1 KERT2-KO mice and assessed barrier function by measuring transepidermal water loss (TEWL) (ref. 36 and Figure 2F). As shown in Figure 2G, TEWL was significantly increased in the back skin of tamoxifen-treated Rab gef1 KERT2-KO mice versus tamoxifen-treated control mice. Consistent with the increased permeability of the skin, the transepidermal passage of a harmless antigen, ovalbumin (OVA), patched on the skin was also potentiated when RABGEF1 was defective in keratinocytes. Indeed, dermal DC uptake and endosomal digestion of OVA was also substantially induced in tamoxifen-treated Rabgef1 KERT2-KO mice, whereas OVA was less accessible to DCs in vehicle-treated Rab gef1 KERT2-KO mice or tamoxifen-treated littermate control mice ( Figure 2H).(DCs) with the capacity to induce a ...

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MyD88: A Critical Adaptor Protein in Innate Immunity Signal Transduction

Cited by 148 publications

References 34 publications

TLR4: The Winding Road to the Discovery of the LPS Receptor

TLR4: The Winding Road to the Discovery of the LPS Receptor

Extracellular stimulation of VSIG4/complement receptor Ig suppresses intracellular bacterial infection by inducing autophagy

Guanine nucleotide exchange factor RABGEF1 regulates keratinocyte-intrinsic signaling to maintain skin homeostasis

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