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Suppressors of cytokine signalling (SOCS) in the immune system

Nature Reviews Immunology volume 2, pages 410–416 (2002)Cite this article

Key Points

  • Several members of the suppressor of cytokine signalling (SOCS) protein family are cytokine-inducible proteins that act in a classical negative-feedback loop to attenuate cytokine signal transduction.

  • SOCS proteins are characterized by a central SRC-homology 2 (SH2) domain, an amino-terminal domain of divergent sequence and a carboxy-terminal conserved SOCS-box domain.

  • The SH2 domains of SOCS proteins interact with activated cytokine receptors and signalling components. SOCS1 is thought to act by means of a direct interaction with Janus kinases (JAKs), which results in the inhibition of tyrosine-kinase activity. Cytokine-induced SH2 protein (CIS) seems to interact with receptors to block the recruitment and activation of signal transducer and activator of transcription (STAT) factors. The action of SOCS3 might combine elements of both of these models.

  • The SOCS-box motif interacts with elongin proteins, which form part of the ubiquitin-mediated proteasomal degradation pathway. So, the inhibitory actions of SOCS proteins seem to combine specific inhibitory interactions with a general mechanism of targeting associated signalling molecules for degradation.

  • Gene-knockout studies have shown that SOCS proteins are indispensable regulators of important physiological systems: SOCS1 is an essential regulator of interferon-γ (IFN-γ) signalling that is crucial to allow the beneficial immunological effects of IFN-γ without the damaging pathological responses. Mice that lack Socs1 die early in life; they have liver disease, inflammatory lesions, lymphopaenia and apoptosis of lymphoid organs, and anomalous T-cell activation.

  • Altered SOCS expression has been associated with inflammatory disease in humans. The manipulation of SOCS-protein function might yield new therapeutic strategies.

Abstract

The suppressors of cytokine signalling (SOCS) are a family of intracellular proteins, several of which have emerged as key physiological regulators of cytokine responses, including those that regulate the immune system. The SOCS proteins seem to regulate signal transduction by combining direct inhibitory interactions with cytokine receptors and signalling proteins with a generic mechanism of targeting associated proteins for degradation. Evidence is emerging for the involvement of SOCS proteins in diseases of the human immune system, which raises the possibility that therapeutic strategies that are based on the manipulation of SOCS activity might be of clinical benefit.

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Figure 1: SOCS proteins are negative-feedback inhibitors of cytokine signal transduction.
Figure 2: The SOCS family of proteins.

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Acknowledgements

Work in my laboratory is supported by the National Health and Medical Research Council, Canberra, Australia; AMRAD Corporation; the National Institutes of Health, Bethesda, USA; and the Australian Federal Government Cooperative Research Centres Program.

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  1. The Walter and Eliza Hall Institute of Medical Research and the Cooperative Research Centre for Cellular Growth Factors, Post Office, Royal Melbourne Hospital, Victoria, 3050, Australia

    Warren S. Alexander

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DATABASES

Cancer.gov

acute lymphoblastic leukaemia

chronic myelogenous leukaemia

non-Hodgkin's lymphoma

Entrez

hepatitis C virus

InterPro

SH2

SOCS box

STAT

LocusLink

BFGF

CIS

Cis

CNTF

CT1

EGF

elongin B

elongin C

erythropoietin

EPOR

G-CSF

GM-CSF

GP130

growth hormone

IFN-γ (human)

IFN-γ (mouse)

IGF1

Igf1

IL-2

IL-4

IL-6

JAK2

Jak3

LIF

M-CSF

NK1.1

OSM

PDGF

PRL

Rag2

SCF

SHP2

SOCS1

Socs1

SOCS2

Socs2

SOCS3

Socs3

SOCS4

SOCS5

SOCS6

SOCS7

STAT3

Stat5a

Stat5b

Stat6

TEL

TNF

Toll-like receptors

TPO

TSLP

VAV

OMIM

Crohn's disease

polycystic kidneys

rheumatoid arthritis

ulcerative colitis

Glossary

SH2 DOMAIN

A protein domain that is found commonly in signal-transduction molecules; it interacts specifically with phosphotyrosine-containing peptides.

UBIQUITIN-MEDIATED PROTEASOMAL DEGRADATION

An important proteolytic process that involves the tagging of unwanted proteins with ubiquitin, which allows their recognition by the proteasome — a large, multi-component protein-degrading complex.

NATURAL KILLER T CELLS

(NKT cells). A subset of T cells that expresses both NK and T-cell markers. In mice, NKT cells were first identified by their expression of the NK1.1 (NKR-P1C) alloantigen. Some mouse NKT cells express an invariant T-cell receptor (TCR) that uses the Vα14 variable region of the TCR α-chain and recognize lipid–CD1d complexes. Similarly, human NKT cells express an invariant Vα24 receptor. NKT cells are characterized functionally by cytolytic activity and the rapid production of cytokines, including IFN-α and IL-4.

γδ T CELLS

T cells express either a T-cell receptor (TCR) that is composed of α- and β-subunits (αβ TCR) or a TCR that is composed of γ- and δ-subunits (γδ TCR). Most (>90%) T cells have an αβ TCR that recognizes conventional MHC class I or II ligands. T cells that express γδ TCRs are less frequent and the ligands of this type of receptor are less well characterized.

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Alexander, W. Suppressors of cytokine signalling (SOCS) in the immune system. Nat Rev Immunol 2, 410–416 (2002). https://doi.org/10.1038/nri818

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