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The cysteine residue of glial fibrillary acidic protein is a critical target for lipoxidation and required for efficient network organization

Journal article
Authors Á Viedma-Poyatos
Yolanda de Pablo
Milos Pekny
D. Pérez-Sala
Published in Free Radical Biology & Medicine
Volume 120
Pages 380-394
ISSN 0891-5849
Publication year 2018
Published at Institute of Neuroscience and Physiology, Department of Clinical Neuroscience
Pages 380-394
Language en
Keywords Astrocytes, Cysteine modification, GFAP, Lipoxidation, Neurodegeneration, Oxidative stress, Protein aggregation, Vimentin, cyclopentenone, cysteine, glial fibrillary acidic protein, heterodimer, prostaglandin, actin filament, animal cell, Article, astrocyte, controlled study, cross linking, electrophilicity, in vitro study, mouse, nonhuman, oxidation, primary cell, priority journal, protein expression, protein modification, protein targeting, residue analysis, SW13 cell line
Subject categories Neurosciences


The type III intermediate filament protein glial fibrillary acidic protein (GFAP) contributes to the homeostasis of astrocytes, where it co-polymerizes with vimentin. Conversely, alterations in GFAP assembly or degradation cause intracellular aggregates linked to astrocyte dysfunction and neurological disease. Moreover, injury and inflammation elicit extensive GFAP organization and expression changes, which underline reactive gliosis. Here we have studied GFAP as a target for modification by electrophilic inflammatory mediators. We show that the GFAP cysteine, C294, is targeted by lipoxidation by cyclopentenone prostaglandins (cyPG) in vitro and in cells. Electrophilic modification of GFAP in cells leads to a striking filament rearrangement, with retraction from the cell periphery and juxtanuclear condensation in thick bundles. Importantly, the C294S mutant is resistant to cyPG addition and filament disruption, thus highlighting the critical role of this residue as a sensor of oxidative damage. However, GFAP C294S shows defective or delayed network formation in GFAP-deficient cells, including SW13/cl.2 cells and GFAP- and vimentin-deficient primary astrocytes. Moreover, GFAP C294S does not effectively integrate with and even disrupts vimentin filaments in the short-term. Interestingly, short-spacer bifunctional cysteine crosslinking produces GFAP-vimentin heterodimers, suggesting that a certain proportion of cysteine residues from both proteins are spatially close. Collectively, these results support that the conserved cysteine residue in type III intermediate filament proteins serves as an electrophilic stress sensor and structural element. Therefore, oxidative modifications of this cysteine could contribute to GFAP disruption or aggregation in pathological situations associated with oxidative or electrophilic stress. © 2018 The Authors

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