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KRIT1 Loss-Of-Function Associated with Cerebral Cavernous Malformation Disease Leads to Enhanced S-Glutathionylation of Distinct Structural and Regulatory Proteins

1
Department of Clinical Sciences (DISCO), Section of Biochemistry, Biology and Physics, Marche Polytechnic University, 60131 Ancona, Italy
2
CCM Italia Research Network, National Coordination Center at the Department of Clinical and Biological Sciences, University of Turin, Orbassano, 10043 Torino, Italy
3
Department of Clinical and Biological Sciences, University of Torino, Orbassano, 10043 Torino, Italy
4
Department of Chemistry, Biology and Biotechnology, University of Perugia, 06123 Perugia, Italy
5
Department of Life and Environmental Sciences (DISVA), Marche Polytechnic University, 60131 Ancona, Italy
6
Proteomics & Mass Spectrometry Laboratory, ISPAAM, National Research Council, 80147 Napoli, Italy
7
Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy
8
Department of Medical Sciences, University of Torino, 10126 Torino, Italy
*
Authors to whom correspondence should be addressed.
These authors share first authorship.
Antioxidants 2019, 8(1), 27; https://doi.org/10.3390/antiox8010027
Received: 5 September 2018 / Revised: 21 December 2018 / Accepted: 11 January 2019 / Published: 17 January 2019
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Abstract

Loss-of-function mutations in the KRIT1 gene are associated with the pathogenesis of cerebral cavernous malformations (CCMs), a major cerebrovascular disease still awaiting therapies. Accumulating evidence demonstrates that KRIT1 plays an important role in major redox-sensitive mechanisms, including transcriptional pathways and autophagy, which play major roles in cellular homeostasis and defense against oxidative stress, raising the possibility that KRIT1 loss has pleiotropic effects on multiple redox-sensitive systems. Using previously established cellular models, we found that KRIT1 loss-of-function affects the glutathione (GSH) redox system, causing a significant decrease in total GSH levels and increase in oxidized glutathione disulfide (GSSG), with a consequent deficit in the GSH/GSSG redox ratio and GSH-mediated antioxidant capacity. Redox proteomic analyses showed that these effects are associated with increased S-glutathionylation of distinct proteins involved in adaptive responses to oxidative stress, including redox-sensitive chaperonins, metabolic enzymes, and cytoskeletal proteins, suggesting a novel molecular signature of KRIT1 loss-of-function. Besides providing further insights into the emerging pleiotropic functions of KRIT1, these findings point definitively to KRIT1 as a major player in redox biology, shedding new light on the mechanistic relationship between KRIT1 loss-of-function and enhanced cell sensitivity to oxidative stress, which may eventually lead to cellular dysfunctions and CCM disease pathogenesis. View Full-Text
Keywords: cerebral cavernous malformations; KRIT1; oxidative stress; altered redox homeostasis and signaling; oxidative post-translational modifications; protein S-glutathionylation; redox proteomics; mass spectrometry cerebral cavernous malformations; KRIT1; oxidative stress; altered redox homeostasis and signaling; oxidative post-translational modifications; protein S-glutathionylation; redox proteomics; mass spectrometry
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Cianfruglia, L.; Perrelli, A.; Fornelli, C.; Magini, A.; Gorbi, S.; Salzano, A.M.; Antognelli, C.; Retta, F.; Benedetti, V.; Cassoni, P.; Emiliani, C.; Principato, G.; Scaloni, A.; Armeni, T.; Retta, S.F. KRIT1 Loss-Of-Function Associated with Cerebral Cavernous Malformation Disease Leads to Enhanced S-Glutathionylation of Distinct Structural and Regulatory Proteins. Antioxidants 2019, 8, 27.

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