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Two discrete promoters regulate the alternatively spliced human interferon regulatory factor-5 isoforms. Multiple
Margo E Mancl1, Guodong Hu, Niquiche Sangster-Guity
1Division of Viral Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
The Journal of Biological Chemistry
|April 5, 2005
Summary
Interferon regulatory factor-5 (IRF-5) generates multiple protein variants that are crucial for immune responses. These IRF-5 isoforms exhibit distinct expression patterns and regulatory mechanisms, influencing type I interferon gene induction.
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- Interferon regulatory factor-5 (IRF-5) is a key regulator of virus-induced immune responses and type I interferon (IFN) gene expression.
- IRF-5 undergoes alternative splicing, producing various isoforms with potentially different functions.
Purpose of the Study:
- To identify and characterize the alternatively spliced isoforms of IRF-5.
- To investigate the differential regulation and cell-type specific expression of these IRF-5 isoforms.
Main Methods:
- Analysis of IRF-5 transcripts in human primary plasmacytoid dendritic cells (PDC) and peripheral blood mononuclear cells (PBMC).
- Identification of distinct transcription start sites and promoter activities for different IRF-5 isoforms.
- Investigation of regulatory elements and transcription factor binding sites within IRF-5 promoters.
Main Results:
- Nine alternatively spliced IRF-5 isoforms (V1-V9) were identified, with distinct expression patterns in different cell types.
- Isoforms V1 and V3 are regulated by separate promoters (P-V1 and P-V3) with distinct regulatory elements.
- P-V1 is constitutively active and stimulated by IRF family members during viral infection, while P-V3 is upregulated by type I IFNs via ISGF3 complex binding.
- Isoforms V5-V9 show specific expression in certain cell types, including cancers.
Conclusions:
- Multiple IRF-5 isoforms exist with unique cell-type specific expression, localization, and regulatory mechanisms.
- These isoforms play diverse roles in virus-mediated type I interferon gene induction, highlighting the complexity of immune regulation.