CARD9 mediates Dectin-1–induced ERK activation by linking Ras-GRF1 to H-Ras for antifungal immunity

Jia, Xiaomin; Tang, Bin; Zhu, Lele; Liu, Yan Hui; Zhao, Xue Qiang; Gorjestani, Sara; Hsu, Yen Michael S.; Yang, Long; Guan, Jian; Xu, Guo; Lin, Xin

doi:10.1084/jem.20132349

Cited by 121 publications

(119 citation statements)

References 64 publications

(107 reference statements)

Supporting

Mentioning

111

Contrasting

Order By: Relevance

“…6G). Our data are consistent with previous observations that ERK signaling is required for the production of TNF␣ and IL-6 downstream of Dectin-1 (30,36). p38 signaling in macrophages and dendritic cells has also been shown to contribute to pro-inflammatory cytokine production (37,38).…”

Section: Discussionsupporting

confidence: 93%

“…PLC␥2 products also activate PKC␦, which then phosphorylates the adaptor protein CARD9, resulting in activation of the NF-B pathway (15). A recent study showed that CARD9 also plays a critical role in ERK activation by bringing together Ras and RasGRF1, resulting in the activation of Ras and ERK further downstream (30). However, the existence of CARD9-independent pathways cannot be ruled out.…”

Section: Discussionmentioning

confidence: 99%

“…In a recent study, activation of the ERK pathway was shown to be critical for inflammatory cytokine production in BMMFs (30). Because we were unable to detect any significant defects in cytokine production in Scimp Ϫ/Ϫ BMDCs during the typical experimental setup, where the readout was measured within the first 24 h of stimulation (data not shown), we focused our analysis on late phases of cytokine production beyond the 24-h time frame.…”

Section: Figure 3 Expression Of Scimp and Its Regulation In Dendritimentioning

confidence: 99%

See 2 more Smart Citations

The Transmembrane Adaptor Protein SCIMP Facilitates Sustained Dectin-1 Signaling in Dendritic Cells

Králová

Fabišik

Pokorná

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

Transmembrane adaptor proteins are molecules specialized in recruiting cytoplasmic proteins to the proximity of the cell membrane as part of the signal transduction process. A member of this family, SLP65/SLP76, Csk-interacting membrane protein (SCIMP), recruits a complex of SLP65/SLP76 and Grb2 adaptor proteins, known to be involved in the activation of PLC␥1/2, Ras, and other pathways. SCIMP expression is restricted to antigen-presenting cells. In a previous cell line-based study, it was shown that, in B cells, SCIMP contributes to the reverse signaling in the immunological synapse, downstream of MHCII glycoproteins. There it mainly facilitates the activation of ERK MAP kinases. However, its importance for MHCII glycoprotein-dependent ERK signaling in primary B cells has not been analyzed. Moreover, its role in macrophages and dendritic cells has remained largely unknown. Here we present the results of our analysis of SCIMP-deficient mice. In these mice, we did not observe any defects in B cell signaling and B cell-dependent responses. On the other hand, we found that, in dendritic cells and macrophages, SCIMP expression is up-regulated after exposure to GM-CSF or the Dectin-1 agonist zymosan. Moreover, we found that SCIMP is strongly phosphorylated after Dectin-1 stimulation and that it participates in signal transduction downstream of this important pattern recognition receptor. Our analysis of SCIMP-deficient dendritic cells revealed that SCIMP specifically contributes to sustaining long-term MAP kinase signaling and cytokine production downstream of Dectin-1 because of an increased expression and sustained phosphorylation lasting at least 24 h after signal initiation.Dectin-1 is a pattern recognition receptor from the C-type lectin receptor family (1). It is expressed in macrophages, dendritic cells, neutrophils, and a subset of T and B cells (2-4). Through its carbohydrate recognition domain, it specifically recognizes ␤-1,3-glucan (5), which is a typical component of fungal cell walls (6). Dectin-1 is considered a major receptor for ␤-glucans and plays an important role in the defense against various species of pathogenic fungi in mice, including Candida albicans, Aspergillus fumigatus, and Pneumocystis carinii (7-11). The importance of dectin-1 for antifungal defense has also been demonstrated by studies of human patients with disrupted dectin-1 function who display increased mucosal colonization with Candida species and suffer from recurrent mucocutaneous fungal infections (12, 13).Dectin-1 signaling is initiated by phosphorylation of the hemITAM motif in its intracellular tail, leading to the recruitment and activation of the protein tyrosine kinase Syk. This is followed by sequential activation of PLC␥2 and PKC␦. Stimulation of this pathway as well as of additional Syk-independent pathways results in the activation of the transcription factors NF-B, nuclear factor of activated T cells (NFAT), and IRF1/5 and initiation of signaling by the MAP kinases ERK, p38, and JNK, which then contribute to downstr...

show abstract

Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Figure 3 Expression Of Scimp and Its Regulation In Dendritimentioning

confidence: 99%

See 1 more Smart Citation

The Transmembrane Adaptor Protein SCIMP Facilitates Sustained Dectin-1 Signaling in Dendritic Cells

Králová

Fabišik

Pokorná

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Dectin-1 signaling regulates ERK (also known as MAP kinase) activity via H-RAS and RAS guanine nucleotide-releasing factor 1 (RASGRF1) (39). This pathway regulates macrophage IL-6, IL-1β, and TNF, but not IL-12 responses, and is protective during systemic candidiasis (39).…”

Section: Introductionmentioning

confidence: 99%

Immunity against fungi

Lionakis¹,

Iliev²,

Hohl³

2017

JCI Insight

109

View full text Add to dashboard Cite

“…Interestingly, Dectin-1 can collaborate with TLRs to orchestrate antifungal immunity. 5 During C. albicans bloodstream infection, which may present as sepsis and septic shock, innate responses govern the early response. Neutrophils are considered principal effector cells conferring protection.…”

mentioning

confidence: 99%

Looking intoCandida albicansinfection, host response, and antifungal strategies

Wang

2015

Virulence

View full text Add to dashboard Cite

CARD9 mediates Dectin-1–induced ERK activation by linking Ras-GRF1 to H-Ras for antifungal immunity

Abstract: CARD9 is dispensable for NF-κB activation induced by Dectin-1 ligands in mice. However, Dectin-1–induced H-Ras activation is mediated by a complex with CARD9, which leads to ERK activation for host innate immune responses to Candida albicans infection.

Cited by 121 publications

References 64 publications

The Transmembrane Adaptor Protein SCIMP Facilitates Sustained Dectin-1 Signaling in Dendritic Cells

The Transmembrane Adaptor Protein SCIMP Facilitates Sustained Dectin-1 Signaling in Dendritic Cells

Immunity against fungi

Looking intoCandida albicansinfection, host response, and antifungal strategies

Contact Info

Product

Resources

About