SOCS2 can enhance interleukin-2 (IL-2) and IL-3 signaling by accelerating SOCS3 degradation

Infection and Immunity Group, Centre for Cancer Research and Cell Biology, Queens University, Belfast, UK.
Molecular and Cellular Biology (Impact Factor: 5.04). 11/2005; 25(20):9115-26. DOI: 10.1128/MCB.25.20.9115-9126.2005
Source: PubMed

ABSTRACT Cytokine responses can be regulated by a family of proteins termed suppressors of cytokine signaling (SOCS) which can inhibit the JAK/STAT pathway in a classical negative-feedback manner. While the SOCS are thought to target signaling intermediates for degradation, relatively little is known about how their turnover is regulated. Unlike other SOCS family members, we find that SOCS2 can enhance interleukin-2 (IL-2)- and IL-3-induced STAT phosphorylation following and potentiate proliferation in response to cytokine stimulation. As a clear mechanism for these effects, we demonstrate that expression of SOCS2 results in marked proteasome-dependent reduction of SOCS3 and SOCS1 protein expression. Furthermore, we provide evidence that this degradation is dependent on the presence of an intact SOCS box and that the loss of SOCS3 is enhanced by coexpression of elongin B/C. This suggests that SOCS2 can bind to SOCS3 and elongin B/C to form an E3 ligase complex resulting in the degradation of SOCS3. Therefore, SOCS2 can enhance cytokine responses by accelerating proteasome-dependent turnover of SOCS3, suggesting a mechanism for the gigantism observed in SOCS2 transgenic mice.

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    • "For SOCS3 analysis in CD4 + cells, equal amounts of total protein were immunoprecipitated with anti- SOCS3 (IBL International) that had been precoupled to protein A Sepharose beads. SOCS3 protein was subsequently analyzed by Western blotting as previously described (Tannahill et al., 2005). Densitometry was performed using ImageJ software (National Institutes of Health). "
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    ABSTRACT: The incidence of allergy and asthma in developed countries is on the increase and this trend looks likely to continue. CD4(+) T helper 2 (Th2) cells are major drivers of these diseases and their commitment is controlled by cytokines such as interleukin 4, which are in turn regulated by the suppressor of cytokine signaling (SOCS) proteins. We report that SOCS2(-/-) CD4(+) T cells show markedly enhanced Th2 differentiation. SOCS2(-/-) mice, as well as RAG-1(-/-) mice transferred with SOCS2(-/-) CD4(+) T cells, exhibit elevated type 2 responses after helminth antigen challenge. Moreover, in in vivo models of atopic dermatitis and allergen-induced airway inflammation, SOCS2(-/-) mice show significantly elevated IgE, eosinophilia, type 2 responses, and inflammatory pathology relative to wild-type mice. Finally, after T cell activation, markedly enhanced STAT6 and STAT5 phosphorylation is observed in SOCS2(-/-) T cells, whereas STAT3 phosphorylation is blunted. Thus, we provide the first evidence that SOCS2 plays an important role in regulating Th2 cell expansion and development of the type 2 allergic responses.
    Journal of Experimental Medicine 06/2011; 208(7):1523-31. DOI:10.1084/jem.20101167 · 13.91 Impact Factor
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    • "Within this context, SOCS2 has been proposed to interact with, and target SOCS3 for proteasomal-mediated degradation. In a cell line-based ectopic expression model, SOCS2 was shown to accelerate SOCS3 degradation, leading to prolonged IL-2 and IL-3 signalling (Piessevaux et al. 2006; Tannahill et al. 2005). If this model reflected physiology, we would predict that in the absence of SOCS2, enhanced or prolonged SOCS3 protein expression would ensue, resulting in curtailed duration and/or intensity of cytokine signalling pathways normally inhibited by SOCS3. "
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    ABSTRACT: Suppressor of cytokine signalling (SOCS) 3 is an essential regulator of cytokine signalling, and in turn its expression is tightly regulated. Data from overexpression studies in cell lines suggest that SOCS2 regulates SOCS3 protein degradation, by forming a molecular bridge to an E3 ubiquitin-ligase complex. Whether this regulation is relevant in primary cells is unknown. In this study, we utilized Socs2( - / - ) mice to examine the role of SOCS2 in modulating SOCS3 expression and degradation, and its impact on interleukin-2 (IL-2) and IL-6 signalling in primary haemopoietic cells. Both biochemical and biological analyses demonstrated unperturbed SOCS3 expression and cytokine signalling in the absence of SOCS2. Our results suggest that SOCS2 is not a physiological regulator of SOCS3 expression and action in primary haemopoietic cells.
    Growth factors (Chur, Switzerland) 10/2009; 27(6):1. DOI:10.1080/08977190903210954 · 3.09 Impact Factor
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    • "A second potential explanation is that relatively strong TCR/CD28 signals may be required to induce a state of heightened cytokine responsiveness. Only cells in which both the IL2Rα and IL2Rβ chain have been upregulated, as well as other positive regulators of IL2R signaling such as Socs2 (Tannahill et al., 2005), will likely be capable of augmenting STAT5 signals to the threshold level required to complete Treg differentiation in WT mice. We suggest that in STAT5b-CA mice, the other factors contributing to enhanced cytokine signaling play a lesser but still important role. "
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    ABSTRACT: Appropriate development of regulatory T (Treg) cells is necessary to prevent autoimmunity. Neonatal mice, unlike adults, lack factors required for Treg cell development. It is unclear what these missing factors are. However, signals emanating from the T cell receptor (TCR), the costimulatory receptor CD28, and the family of gammac-dependent cytokine receptors are required for Treg cell development. Herein we demonstrate that expression of a constitutively active Stat5b transgene (Stat5b-CA) allowed for Treg cell development in neonatal mice and restored Treg cell numbers in Cd28(-/-) mice. Sequence analysis of TCR genes in Stat5b-CA Treg cells indicated that ectopic STAT5 activation resulted in a TCR repertoire that more closely resembled that of naive T cells. Using MHCII tetramers to identify antigen-specific T cells, we showed that STAT5 signals diverted thymocytes normally destined to become naive T cells into the Treg cell lineage. Our data support a two-step model of Treg cell differentiation in which TCR and CD28 signals induce cytokine responsiveness and STAT5-inducing cytokines then complete the program of Treg cell differentiation.
    Immunity 02/2008; 28(1):112-21. DOI:10.1016/j.immuni.2007.11.022 · 19.75 Impact Factor
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