Inhibition of IL-6 family cytokines by SOCS3 - PubMed (original) (raw)

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Inhibition of IL-6 family cytokines by SOCS3

Jeffrey J Babon et al. Semin Immunol. 2014 Feb.

Abstract

IL-6 a multi-functional cytokine with important effects in both inflammation and haematopoiesis. SOCS3 is the primary inhibitor of IL-6 signalling, interacting with gp130, the common shared chain of the IL-6 family of cytokines, and JAK1, JAK2 and TYK2 to control both the duration of signalling and the biological response. Recent biochemical and structural studies have shown SOCS3 binds to only these three JAKs, all of which are associated with IL-6 signalling, and not JAK3. This specificity is determined by a three residue "GQM" motif in the kinase domain of JAK1, JAK2 and TYK2. SOCS3 binds to JAK and gp130 simultaneously, and inhibits JAK activity in an ATP-independent manner by partially occluding the kinase's substrate binding groove with its kinase inhibitory region. We therefore propose a model in which each of gp130, JAK and SOCS3 are directly bound to the other two, allowing SOCS3 to inhibit IL6 signalling with high potency and specificity.

Keywords: Cytokine signalling; IL-6; JAK/STAT; Janus Kinases; SOCS.

Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.

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Figures

Figure 1

Figure 1. IL-6 signalling and its inhibition

Schematic diagram illustrating activation (left) of the JAK/STAT signalling cascade in response to IL-6 and the termination of signalling (right) catalysed by SOCS3. IL-6 signals via a cell-surface receptor that consists of a 2:2 gp130(blue):IL-6Rα (orange) tetramer. Interaction between the cytokine and its receptor induces the autoactivation (in trans) of Janus Kinases (JAKs,: JAK1, JAK2, TYK2; shown in beige) bound to the cytoplasmic domain of gp130. Activated JAK then phosphorylates five tyrosines within gp130cyt. Four of these phosphotyrosines recruit STAT3 or STAT1/STAT3 which are then themselves phosphorylated, and thereby activated, by JAK, translocate to the nucleus and begin inducing the transcription of IL-6-responsive genes. STATs also upregulate the transcription of SOCS3 (red) which binds to the fifth phosphotyrosine in gp130cyt (pY759) and shuts down the JAK/STAT signalling cascade by binding to JAK and directly inhibiting its catalytic activity, forming a negative feedback loop. This phosphotyrosine also recruits SHP-2, which leads to activation of the MAPK/ERK and PI3K pathways (not shown here) and therefore SOCS3, which competes for this site, is also capable of inhibiting those signalling cascades. Signalling and inhibition is symmetric with respect to both gp130 chains and is shown here divided into left and right for ease of illustration. The structures shown are those solved and/or modelled for components of the signalling cascade, Note that the pseudokinase and SH2-like domains of JAK are omitted for clarity in this figure.

Figure 2

Figure 2. SOCS3 inhibits the duration of IL-6 signalling by direct inhibition of JAK1, JAK2 and TYK2 but not JAK3

(A) Schematic diagram showing the effect of SOCS3 on STAT1 and STAT3 activation post IL-6 stimulation. Shown is a representation of the data from[46] (B). The structure of SOCS3 (PDB 4GL9) with an explanation of the major functional motifs shown as a schematic below. Note that the PEST motif is absent from the structure and that the SOCS box has been modelled based on the structure of the SOCS2 SOCS box (PDB 2C9W). (C) SOCS3 (red) binds the kinase domains of JAK1, JAK2 and TYK2 and inhibits its catalytic activity by blocking the substrate binding site with its kinase inhibitory region (black). Note that SOCS3 remains bound to gp130 (blue) whilst in complex with JAK (beige) and that ATP binding is unaffected.

Figure 3

Figure 3

SOCS3 inhibits IL-6 family signalling by targeting a gp130:JAK dimer.

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