Abstract
Accumulating evidence demonstrates that cytokine receptor signaling is negatively regulated by a family of Src homology 2 domain-containing adaptor molecules termed SOCS (suppressor of cytokine signaling). Previous studies have indicated that the expression of SOCS-related molecules is tightly controlled at the level of transcription. Furthermore, it has been reported that SOCS polypeptides are relatively unstable in cells, unless they are associated with elongins B and C. Herein, we document the existence of a third mechanism of regulation of SOCS function. Our data showed that expression of SOCS-1, a member of the SOCS family, is strongly repressed at the level of translation initiation. Structure-function analyses indicated that this effect is mediated by the 5' untranslated region of socs-1 and that it relates to the presence of two upstream AUGs in this region. Further studies revealed that socs-1 translation is cap-dependent and that it is modulated by eIF4E-binding proteins. In combination, these results uncover a novel level of regulation of SOCS-related molecules. Moreover, coupled with previous findings, they suggest that SOCS expression is tightly regulated through multiple mechanisms, in order to avoid inappropriate interference with cytokine-mediated effects.
Highlights
Cytokines such as interleukins (ILs)1 and interferons (IFNs) play pivotal roles in a wide spectrum of processes [1,2,3]
Lysates from mouse thymus and IL-2-treated CTLL-2 T-cells were immunoprecipitated with a polyclonal rabbit antiserum directed against the carboxyl-terminal portion of SOCS-1, and the presence of SOCS-1 in these immunoprecipitates was revealed by immunoblotting with another antibody raised against the aminoterminal segment of SOCS-1 (Fig. 1A)
Socs-1 transcripts could be readily documented in these samples (Fig. 1B), we found that the SOCS-1 protein was very difficult to detect under standard immunoprecipitation conditions
Summary
Cytokines such as interleukins (ILs) and interferons (IFNs) play pivotal roles in a wide spectrum of processes [1,2,3] They are required for normal hemopoietic cell development and immunity. As is the case for many other receptors, engagement of these receptors triggers the tyrosine phosphorylation of cellular proteins, including the cytokine receptors themselves, members of the Jak family of proteintyrosine kinases, and the STAT transcription factors. Mice lacking the prototype of the family, SOCS-1, exhibit monocytic and polymorphonuclear infiltration of several organs, fatty degeneration of the liver, and early neonatal lethality [23, 24] Their hemopoietic cell progenitors have an increased sensitivity to cytokines like granulocyte-macrophage colony-stimulating factor and IFN-␥ [25]. These animals possess markedly diminished cellularity in the thymus, seemingly as a consequence of enhanced apoptosis [38]
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