Expression of leukemia inhibitory factor in Müller glia cells is regulated by a redox-dependent mRNA stability mechanism.
- Agca C Department of Ophthalmology, Lab for Retinal Cell Biology, University of Zurich, Wagistrasse 14, Zurich, 8091, Switzerland. cavitagca@gmail.com.
- Boldt K Division of Experimental Ophthalmology and Medical Proteome Center, Centre for Ophthalmology, University of Tübingen, 72076, Tübingen, Germany. karsten.boldt@uni-tuebingen.de.
- Gubler A Department of Ophthalmology, Lab for Retinal Cell Biology, University of Zurich, Wagistrasse 14, Zurich, 8091, Switzerland. andrea.gubler@usz.ch.
- Meneau I Department of Ophthalmology, Lab for Retinal Cell Biology, University of Zurich, Wagistrasse 14, Zurich, 8091, Switzerland. isabelle.meneau@usz.ch.
- Corpet A Department of Gynecology, University of Zurich, Zurich, 8091, Switzerland. armelle.corpet@univ-lyon1.fr.
- Samardzija M Department of Ophthalmology, Lab for Retinal Cell Biology, University of Zurich, Wagistrasse 14, Zurich, 8091, Switzerland. samam@usz.uzh.ch.
- Stucki M Department of Gynecology, University of Zurich, Zurich, 8091, Switzerland. manuel.stucki@usz.ch.
- Ueffing M Division of Experimental Ophthalmology and Medical Proteome Center, Centre for Ophthalmology, University of Tübingen, 72076, Tübingen, Germany. Marius.Ueffing@uni-tuebingen.de.
- Grimm C Department of Ophthalmology, Lab for Retinal Cell Biology, University of Zurich, Wagistrasse 14, Zurich, 8091, Switzerland. cgrimm@opht.uzh.ch.
- 2015-04-25
Published in:
- BMC biology. - 2015
Animals
Cell Line
Ependymoglial Cells
Gene Expression Regulation
Hydrogen Peroxide
Leukemia Inhibitory Factor
Mice
Oxidation-Reduction
RNA Stability
Rats
Retina
Retinal Degeneration
Signal Transduction
English
BACKGROUND
Photoreceptor degeneration is a main hallmark of many blinding diseases making protection of photoreceptors crucial to prevent vision loss. Thus, regulation of endogenous neuroprotective factors may be key for cell survival and attenuation of disease progression. Important neuroprotective factors in the retina include H2O2 generated by injured photoreceptors, and leukemia inhibitory factor (LIF) expressed in Müller glia cells in response to photoreceptor damage.
RESULTS
We present evidence that H2O2 connects to the LIF response by inducing stabilization of Lif transcripts in Müller cells. This process was independent of active gene transcription and p38 MAPK, but relied on AU-rich elements (AREs), which we identified within the highly conserved Lif 3'UTR. Affinity purification combined with quantitative mass spectrometry identified several proteins that bound to these AREs. Among those, interleukin enhancer binding factor 3 (ILF3) was confirmed to participate in the redox-dependent Lif mRNA stabilization. Additionally we show that KH-type splicing regulatory protein (KHSRP) was crucial for maintaining basal Lif expression levels in non-stressed Müller cells.
CONCLUSIONS
Our results suggest that H2O2-induced redox signaling increases Lif transcript levels through ILF3 mediated mRNA stabilization. Generation of H2O2 by injured photoreceptors may thus enhance stability of Lif mRNA and therefore augment neuroprotective LIF signaling during degenerative conditions in vivo.
Photoreceptor degeneration is a main hallmark of many blinding diseases making protection of photoreceptors crucial to prevent vision loss. Thus, regulation of endogenous neuroprotective factors may be key for cell survival and attenuation of disease progression. Important neuroprotective factors in the retina include H2O2 generated by injured photoreceptors, and leukemia inhibitory factor (LIF) expressed in Müller glia cells in response to photoreceptor damage.
RESULTS
We present evidence that H2O2 connects to the LIF response by inducing stabilization of Lif transcripts in Müller cells. This process was independent of active gene transcription and p38 MAPK, but relied on AU-rich elements (AREs), which we identified within the highly conserved Lif 3'UTR. Affinity purification combined with quantitative mass spectrometry identified several proteins that bound to these AREs. Among those, interleukin enhancer binding factor 3 (ILF3) was confirmed to participate in the redox-dependent Lif mRNA stabilization. Additionally we show that KH-type splicing regulatory protein (KHSRP) was crucial for maintaining basal Lif expression levels in non-stressed Müller cells.
CONCLUSIONS
Our results suggest that H2O2-induced redox signaling increases Lif transcript levels through ILF3 mediated mRNA stabilization. Generation of H2O2 by injured photoreceptors may thus enhance stability of Lif mRNA and therefore augment neuroprotective LIF signaling during degenerative conditions in vivo.
- Language
-
- English
- Open access status
- gold
- Identifiers
-
- DOI 10.1186/s12915-015-0137-1
- PMID 25907681
- Persistent URL
- https://sonar.ch/global/documents/298396
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