Expression of leukemia inhibitory factor in Müller glia cells is regulated by a redox-dependent mRNA stability mechanism

BMC Biology

Research Article

Manuel Stucki¹  Armelle Corpet²  Isabelle Meneau³  Andrea Gubler³  Marijana Samardzija³  Cavit Agca⁴  Christian Grimm⁵  Karsten Boldt⁶  Marius Ueffing⁶ 

[1] Department of Gynecology, University of Zurich, 8091, Zurich, Switzerland;Department of Gynecology, University of Zurich, 8091, Zurich, Switzerland;Present address: Center for Molecular and Cellular Physiology and Genetics, University Lyon I, Villeurbanne, France;Department of Ophthalmology, Lab for Retinal Cell Biology, University of Zurich, Wagistrasse 14, 8091, Zurich, Switzerland;Department of Ophthalmology, Lab for Retinal Cell Biology, University of Zurich, Wagistrasse 14, 8091, Zurich, Switzerland;Present address: Department of Biomedicine, University Hospital Basel, 4031, Basel, Switzerland;Department of Ophthalmology, Lab for Retinal Cell Biology, University of Zurich, Wagistrasse 14, 8091, Zurich, Switzerland;Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, 8091, Zurich, Switzerland;Neuroscience Center (ZNZ), University of Zurich, 8091, Zurich, Switzerland;Division of Experimental Ophthalmology and Medical Proteome Center, Centre for Ophthalmology, University of Tübingen, 72076, Tübingen, Germany;

关键词: LIF;    Redox signaling;    mRNA stability;    Retina;    Müller glial cells;    ILF3;    KHSRP;    p38 MAPK;    Neuroprotection;   

DOI  :  10.1186/s12915-015-0137-1

 received in 2015-01-07, accepted in 2015-04-08,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundPhotoreceptor 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.ResultsWe 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.ConclusionsOur 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.

【 授权许可】

Unknown   
© Agca et al. 2015. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.