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A nuclear target for interleukin-1alpha: interaction with the growth suppressor necdin modulates proliferation and
Bo Hu1, Shuhui Wang, Yingze Zhang
1Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh School of Medicine, Biomedical Science Tower South Wing, 7th Floor, 3500 Terrace Street, Pittsburgh, PA 15261, USA.
Abstract:
There is growing evidence for the intracellular role of cytokines and growth factors, but the pathways by which these activities occur remain largely obscure. Previous work from our laboratory identified the constitutive, aberrant expression of the 31-kDa IL-1 alpha precursor (pre-IL-1 alpha) in the nuclei of fibroblasts from the lesional skin of patients with systemic sclerosis (SSc). We established that pre-IL-1 alpha expression was associated with increased fibroblast proliferation and collagen production. Further investigation has led to the identification of a mechanism by which nuclear expression of pre-IL-1 alpha affects fibroblast growth and matrix production. By using a yeast two-hybrid method, we found that pre-IL-1 alpha binds necdin, a nuclear protein with growth suppressor activity. We mapped the region of pre-IL-1 alpha responsible for necdin binding and found it to be localized near the N terminus, a region that is present on pre-IL-1 alpha, but not the mature 17-kDa cytokine. Expression studies demonstrated that pre-IL-1 alpha associates with necdin in the nuclei of mammalian cell lines and regulates cell growth and collagen expression. Our results provide the first evidence, to our knowledge, of a nuclear target for pre-IL-1 alpha. Based on these findings, we propose that the constitutively up-regulated expression of pre-IL-1 alpha in the nuclei of SSc fibroblasts up-regulates proliferation and matrix production of SSc fibroblasts through binding necdin, and by counteracting its effects on cell growth and collagen production.
Insights
Systemic sclerosis (SSc) fibroblasts exhibit nuclear interleukin-1 alpha precursor (pre-IL-1α), driving proliferation and collagen production. This study identifies necdin as a nuclear binding partner of pre-IL-1α, revealing a novel mechanism for SSc pathogenesis.
Area of Science:
- Cell Biology
- Molecular Biology
- Dermatology
Background:
- Cytokines and growth factors have intracellular roles, but the underlying mechanisms are unclear.
- Constitutive nuclear expression of interleukin-1 alpha precursor (pre-IL-1α) is observed in lesional skin fibroblasts of systemic sclerosis (SSc) patients.
- Nuclear pre-IL-1α is linked to increased fibroblast proliferation and collagen production in SSc.
Purpose of the Study:
- To elucidate the mechanism by which nuclear pre-IL-1α influences fibroblast growth and matrix production.
- To identify nuclear targets and binding partners of pre-IL-1α.
- To understand the role of pre-IL-1α-necdin interaction in SSc fibroblast behavior.
Main Methods:
- Yeast two-hybrid screening to identify pre-IL-1α binding proteins.
- N-terminal mapping of the pre-IL-1α region responsible for necdin binding.
- Expression studies in mammalian cell lines to confirm nuclear association and functional effects.
Main Results:
- Pre-IL-1α binds to necdin, a nuclear protein with growth suppressor activity.
- The necdin-binding region of pre-IL-1α is located near its N terminus.
- Nuclear association of pre-IL-1α and necdin regulates cell growth and collagen expression in mammalian cells.
Conclusions:
- This study identifies necdin as the first nuclear target of pre-IL-1α.
- Constitutively upregulated nuclear pre-IL-1α in SSc fibroblasts promotes proliferation and matrix production by binding and counteracting necdin's suppressive effects.
- This interaction presents a novel pathway contributing to SSc pathogenesis.