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Regulation of SOCS-1 expression by translational repression
A Gregorieff1, S Pyronnet, N Sonenberg
1McGill Cancer Centre and the Departments of Biochemistry, Oncology, and Medicine, McGill University, Montréal, Québec H3G 1Y6, Canada.
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.
Insights
Suppressor of cytokine signaling (SOCS) expression is regulated by multiple mechanisms. This study reveals a novel translational repression of SOCS-1, mediated by its 5' untranslated region, adding another layer to cytokine signaling control.
Area of Science:
- Molecular Biology
- Immunology
- Cell Signaling
Background:
- Cytokine receptor signaling is crucial for cellular communication and immune responses.
- Suppressor of cytokine signaling (SOCS) proteins are key negative regulators of cytokine signaling.
- Existing regulatory mechanisms for SOCS expression include transcriptional control and protein stability via elongins B and C.
Purpose of the Study:
- To investigate novel regulatory mechanisms controlling SOCS protein expression.
- To elucidate the role of translational control in SOCS-1 regulation.
- To identify the specific elements within SOCS-1 responsible for translational repression.
Main Methods:
- Analysis of SOCS-1 gene expression and protein levels.
- Structure-function analysis of the 5' untranslated region (UTR) of socs-1.
- Investigation of cap-dependent translation and modulation by eIF4E-binding proteins.
Main Results:
- SOCS-1 expression is significantly repressed at the level of translation initiation.
- The 5' UTR of socs-1, containing two upstream AUGs, mediates this translational repression.
- SOCS-1 translation is cap-dependent and influenced by eIF4E-binding proteins.
Conclusions:
- A novel mechanism of translational repression regulates SOCS-1 expression.
- Multiple regulatory layers, including translation, ensure precise control of SOCS expression.
- This intricate regulation prevents inappropriate interference with cytokine-mediated effects and maintains immune homeostasis.