Transmembrane adaptor SCIMP is more important than previously thought

A structurally interesting family of leukocyte membrane proteins are so called transmembrane adaptor proteins (TRAPs). These proteins posses a short extracellular segment, a single transmembrane domain and major intracellular part containing motifs potentially involved in interactions with other intracellular proteins. Leukocyte TRAPs can be divided into three subfamilies: immunoreceptor-associated TRAPs (TCRζ, FcRγ, DAP10, DAP12), palmitoylated TRAPs (LAT, PAG/Cbp, NTAL/LAB, LIME, PRR7, SCIMP, LST1/A, GAPT, WBP1L), and TRAPs that are neither directly associated with any immunoreceptor nor palmitoylated (e.g. LAX, SIT, TRIM) (1, 2). The localization of most TRAPs to the plasma membrane predisposes them to act in the proximal events of various signaling pathways, either as positive or negative regulators of signaling. The palmitoylated TRAPs interact with so called membrane rafts, nanodomains of specific protein and lipid composition.

SCIMP (SLP adaptor and C-terminal Src kinase (CSK)-interacting membrane protein) is expressed in various leukocytes capable of antigen presentation. It was demonstrated to be involved in Erk1/2 signaling downstream of major histocompatibility complex type II (MHC II) and dectin-1 receptors in B cells and dendritic cells (3, 4). SCIMP associated with TLR4 or other cell-surface and intracellular TLRs also participates in initiation of production of pro-inflammatory cytokines (5) and is involved in inflammasome-driven IL-1β production (6).

Fig. 1: SCIMP is a spatiotemporal transmembrane scaffold for Erk1/2 to direct pro-inflammatory signaling in TLR-activated macrophages. From Lucas RM et al., Cell Rep. 4, 109662 (7).

However, until recently the role of the Erk1/2 kinases in TLR signaling remained rather unclear, because this important signaling pathway is apparently involved both in pro- and anti-inflammatory responses.

The most recent study (7) reveals, by means of high-resolution, live-cell imaging and using SCIMP KO mice, that SCIMP serves as a scaffold for Erk1/2 in TLR pathways, which guides the recruitment of Erk2 to membrane ruffles and macropinosomes essential for pro-inflammatory TLR4 signaling. SCIMP-deficient mice are defective in Erk1/2 recruitment to TLR4, c-Fos activation, and pro-inflammatory cytokine production.


Thus, SCIMP appears to be a key, well defined component in initiation TLR-mediated pro-inflammatory responses in macrophages.

Prof. Václav Hořejší, PhD
Inst. of Molecular Genetics AS CR
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References:
1. Horejsı, V., Zhang, W., and Schraven, B. (2004). Transmembrane adaptor proteins: organizers of immunoreceptor signalling. Nat. Rev. Immunol. 4, 603–616.
2. Stepanek, O., Draber, P., and Horejsi, V. (2014). Palmitoylated transmembrane adaptor proteins in leukocyte signaling. Cell. Signal. 26, 895–902.
3. Draber, P., Vonkova, I., Stepanek, O., Hrdinka, M., Kucova, M., Skopcova, T., Otahal, P., Angelisova, P., Horejsi, V., Yeung, M., et al. (2011). SCIMP, a transmembrane adaptor protein involved in major histocompatibility complex class II signaling. Mol. Cell. Biol. 31, 4550–4562.
4. Kralova, J., Fabisik, M., Pokorna, J., Skopcova, T., Malissen, B., and Brdicka,T. (2016). The transmembrane adaptor protein SCIMP facilitates sustained dectin-1 signaling in dendritic cells. J. Biol. Chem. 291, 16530–16540.
5. Luo, L., Bokil, N.J., Wall, A.A., Kapetanovic, R., Lansdaal, N.M., Marceline, F., Burgess, B.J., Tong, S.J., Guo, Z., Alexandrov, K., et al. (2017). SCIMP is a transmembrane non-TIR TLR adaptor that promotes proinflammatory cytokine production from macrophages. Nat. Commun. 8, 14133.
6. Zewinger, S., Reiser, J., Jankowski, V., Alansary, D., Hahm, E., Triem, S., Klug, M., Schunk, S.J., Schmit, D., Kramann, R., et al. (2020). Apolipoprotein C3 induces inflammation and organ damage by alternative inflammasome activation. Nat. Immunol. 21, 30–41.
7. Lucas, R.M., Liu, L., Curson, J.E.B., Koh,Y.W.H., Tuladhar, N., Condon, N.D., Das Gupta, K., Burgener, S.S., Schroder, K., Ingley, E., Sweet, M.J., Stow, J.L., Luo, L. (2021). SCIMP is a spatiotemporal transmembrane scaffold for Erk1/2 to direct pro-inflammatory signaling in TLR-activated macrophages. Cell Rep. 4, 109662.