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

Abstract

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...

SCIMP is a transmembrane non-TIR TLR adaptor that promotes proinflammatory cytokine production from macrophages

“…5e). This finding is consistent with a recent study, which found no role for MyD88 in SCIMP responses downstream of zymosan19. The concentration of SCIMP in cell surface ruffles and projections and its fractionation in detergent-resistant membrane fractions (Fig.…”

“…The most recently described member of the pTRAP family is SLP adaptor and C-terminal Src kinase (CSK)-interacting membrane protein (SCIMP), which has been reported to associate with Src family kinases (SFKs) and to regulate MHC class II signalling in B cells18 and Dectin-1 signalling in dendritic cells19. Recent evidence also posits SCIMP as a potential disease-related gene in human autoimmune and neurodegenerative conditions2021.…”

Development of SH2 probes and pull‐down assays to detect pathogen‐induced, site‐specific tyrosine phosphorylation of the TLR adaptor SCIMP

“…SCIMP is a palmitoylated transmembrane adaptor protein (TRAP) and a scaffold for Src family kinases (SFKs) and other signaling proteins 12 . SCIMP is immune‐restricted, and has been implicated in signaling in both B cells 12 and dendritic cells 13 . We recently revealed a prominent function in macrophages, where SCIMP acts as a membrane‐anchored adaptor for Toll‐like receptors (TLRs).…”

“…12 SCIMP is immune-restricted, and has been implicated in signaling in both B cells 12 and dendritic cells. 13 We recently revealed a prominent function in macrophages, where SCIMP acts as a membrane-anchored adaptor for Toll-like receptors (TLRs). SCIMP scaffolds SFKs for TLR4 phosphorylation and regulates downstream signaling to elicit highly selective proinflammatory cytokine production.…”

pTRAPs: Transmembrane adaptors in innate immune signaling

“…MHC‐II antibody crosslinking experiments on SCIMP‐silenced and reconstituted B cell lines provided evidence for SCIMP as both a positive and negative regulator of ERK1/2 signaling, with the initial potentiation of this response by SCIMP countered by its subsequent binding of Csk to downregulate the response . More recent studies with Scimp −/− mice suggest that this pTRAP is not absolutely necessary for an MHC‐II response in B cells . Given the literature on the role of pTRAPs in FcεRI signaling in mast cells (above), it seems likely that additional pTRAP family member(s) could play a compensatory role in the absence of SCIMP.…”