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Suppressor of cytokine signaling 1 negatively regulates Toll-like receptor signaling by mediating Mal degradation

Abstract

Toll-like receptor (TLR) signals that initiate innate immune responses to pathogens must be tightly regulated to prevent excessive inflammatory damage to the host. The adaptor protein Mal is specifically involved in signaling via TLR2 and TLR4. We demonstrate here that after TLR2 and TLR4 stimulation Mal becomes phosphorylated by Bruton's tyrosine kinase (Btk) and then interacts with SOCS-1, which results in Mal polyubiquitination and subsequent degradation. Removal of SOCS-1 regulation potentiates Mal-dependent p65 phosphorylation and transactivation of NF-κB, leading to amplified inflammatory responses. These data identify a target of SOCS-1 that regulates TLR signaling via a mechanism distinct from an autocrine cytokine response. The transient activation of Mal and subsequent SOCS-1–mediated degradation is a rapid and selective means of limiting primary innate immune response.

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Figure 1: Mal contains a PEST domain which targets it for TLR-mediated degradation.
Figure 2: Mal interacts with SOCS-1 and undergoes SOCS-1–mediated degradation.
Figure 3: SOCS-1 specifically promotes polyubiquitination of Mal.
Figure 4: Tyrosine phosphorylation by Btk is required to facilitate TLR-induced degradation of Mal.
Figure 5: Mal undergoes polyubiquitination on Lys 15 and 16 by SOCS-1, the dysregulation of which induces a potentiated NF-κB response.
Figure 6: SOCS-1 negative regulation of Mal controls the transient transactivation of NF-κB.

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Acknowledgements

We thank T. Lang, J. Kiu and K. Palmer for technical assistance. Supported by the National Health and Medical Research Council (334023 to A.M., 236866 to P.C. and 284220 to P.J.H.), Science Foundation Ireland and the Cooperative Research Centre for Oral Health Sciences (R.S.).

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Correspondence to Paul J Hertzog.

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Supplementary information

Supplementary Fig. 1

Schematic diagram illustrating the location within the N-terminal of the proline, glutamic acid, serine and threonine (PEST) rich domain located between residues human Mal (36-72) and murine Mal (43-76), proximal to their respective TIR domains; hMal (75-235), mMal (94-241). (PDF 125 kb)

Supplementary Fig. 2

Schematic diagram illustrating a role for Mal in mediating p65Ser536 phosphorylation of NF-κB, thereby inducing transcriptional activation of NF-κB, and its negative regulation by SOCS-1. (PDF 60 kb)

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Mansell, A., Smith, R., Doyle, S. et al. Suppressor of cytokine signaling 1 negatively regulates Toll-like receptor signaling by mediating Mal degradation. Nat Immunol 7, 148–155 (2006). https://doi.org/10.1038/ni1299

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