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1. Author Correction: Mitophagy curtails cytosolic mtDNA-dependent activation of cGAS/STING inflammation during aging

Author

Jiménez-Loygorri, Juan Ignacio [0000-0002-3065-9952], Villarejo-Zori, Beatriz [0000-0002-5502-4793], Viedma-Poyatos, Álvaro [0000-0003-4920-6328], Zapata-Muñoz, Juan [0000-0003-4747-920X], Benítez-Fernández, Rocío [0000-0003-3535-4370], Frutos-Lisón, M.D. [0000-0002-7899-5744], Tomás-Barberán, Francisco Abraham [0000-0002-0790-1739], Espín, Juan Carlos [0000-0002-1068-8692], Area-Gomez, Estela [0000-0002-0962-1570], Gómez-Durán, Aurora [0000-0002-5895-6860], Boya, Patricia [0000-0003-3045-951X], Jiménez-Loygorri, Juan Ignacio, Villarejo-Zori, Beatriz, Viedma-Poyatos, Álvaro, Zapata-Muñoz, Juan, Benítez-Fernández, Rocío, Frutos-Lisón, M.D., Tomás Barberán, Francisco, Espín de Gea, Juan Carlos, Area-Gomez, Estela, Gómez-Durán, Aurora, Boya, Patricia, Jiménez-Loygorri, Juan Ignacio [0000-0002-3065-9952], Villarejo-Zori, Beatriz [0000-0002-5502-4793], Viedma-Poyatos, Álvaro [0000-0003-4920-6328], Zapata-Muñoz, Juan [0000-0003-4747-920X], Benítez-Fernández, Rocío [0000-0003-3535-4370], Frutos-Lisón, M.D. [0000-0002-7899-5744], Tomás-Barberán, Francisco Abraham [0000-0002-0790-1739], Espín, Juan Carlos [0000-0002-1068-8692], Area-Gomez, Estela [0000-0002-0962-1570], Gómez-Durán, Aurora [0000-0002-5895-6860], Boya, Patricia [0000-0003-3045-951X], Jiménez-Loygorri, Juan Ignacio, Villarejo-Zori, Beatriz, Viedma-Poyatos, Álvaro, Zapata-Muñoz, Juan, Benítez-Fernández, Rocío, Frutos-Lisón, M.D., Tomás Barberán, Francisco, Espín de Gea, Juan Carlos, Area-Gomez, Estela, Gómez-Durán, Aurora, and Boya, Patricia

Abstract

The original version of this article contained an error in Fig. 7a. The representative image for ABT-737+QVD+UA (Scr-siRNA) was inadvertently duplicated from the image for Control. The image for ABT-737+QVD+UA (Scr-siRNA) has been replaced with a correct image. This has now been corrected in the HTML and PDF version of this Article.

Published
2024

2. Mitophagy curtails cytosolic mtDNAdependent activation of cGAS/STING inflammation during aging

Author

Swiss National Science Foundation, Ministerio de Ciencia e Innovación (España), European Commission, Consejo Superior de Investigaciones Científicas (España), Jiménez-Loygorri, Juan Ignacio [0000-0002-3065-9952], Villarejo-Zori, Beatriz [0000-0002-5502-4793], Viedma-Poyatos, Álvaro [0000-0003-4920-6328], Zapata-Muñoz, Juan [0000-0003-4747-920X], Benítez-Fernández, Rocío [0000-0003-3535-4370], Frutos-Lisón, M.D. [0000-0002-7899-5744], Tomás-Barberán, Francisco Abraham [0000-0002-0790-1739], Espín, Juan Carlos [0000-0002-1068-8692], Area-Gomez, Estela [0000-0002-0962-1570], Gómez-Durán, Aurora [0000-0002-5895-6860], Boya, Patricia [0000-0003-3045-951X], Jiménez-Loygorri, Juan Ignacio, Villarejo-Zori, Beatriz, Viedma-Poyatos, Álvaro, Zapata-Muñoz, Juan, Benítez-Fernández, Rocío, Frutos-Lisón, M.D., Tomás Barberán, Francisco, Espín de Gea, Juan Carlos, Area-Gomez, Estela, Gómez-Durán, Aurora, Boya, Patricia, Swiss National Science Foundation, Ministerio de Ciencia e Innovación (España), European Commission, Consejo Superior de Investigaciones Científicas (España), Jiménez-Loygorri, Juan Ignacio [0000-0002-3065-9952], Villarejo-Zori, Beatriz [0000-0002-5502-4793], Viedma-Poyatos, Álvaro [0000-0003-4920-6328], Zapata-Muñoz, Juan [0000-0003-4747-920X], Benítez-Fernández, Rocío [0000-0003-3535-4370], Frutos-Lisón, M.D. [0000-0002-7899-5744], Tomás-Barberán, Francisco Abraham [0000-0002-0790-1739], Espín, Juan Carlos [0000-0002-1068-8692], Area-Gomez, Estela [0000-0002-0962-1570], Gómez-Durán, Aurora [0000-0002-5895-6860], Boya, Patricia [0000-0003-3045-951X], Jiménez-Loygorri, Juan Ignacio, Villarejo-Zori, Beatriz, Viedma-Poyatos, Álvaro, Zapata-Muñoz, Juan, Benítez-Fernández, Rocío, Frutos-Lisón, M.D., Tomás Barberán, Francisco, Espín de Gea, Juan Carlos, Area-Gomez, Estela, Gómez-Durán, Aurora, and Boya, Patricia

Abstract

Macroautophagy decreases with age, and this change is considered a hallmark of the aging process. It remains unknown whether mitophagy, the essential selective autophagic degradation of mitochondria, also decreases with age. In our analysis of mitophagy in multiple organs in the mito-QC reporter mouse, mitophagy is either increased or unchanged in old versus young mice. Transcriptomic analysis shows marked upregulation of the type I interferon response in the retina of old mice, which correlates with increased levels of cytosolic mtDNA and activation of the cGAS/STING pathway. Crucially, these same alterations are replicated in primary human fibroblasts from elderly donors. In old mice, pharmacological induction of mitophagy with urolithin A attenuates cGAS/STING activation and ameliorates deterioration of neurological function. These findings point to mitophagy induction as a strategy to decrease age-associated inflammation and increase healthspan.

Published
2024

3. Mitophagy in the retina: Viewing mitochondrial homeostasis through a new lens

Author

Ministerio de Ciencia e Innovación (España), University of Fribourg, Swiss National Science Foundation, Jiménez-Loygorri, Juan Ignacio [0000-0002-3065-9952], Benítez-Fernández, Rocío [0000-0003-3535-4370], Viedma-Poyatos, Álvaro [0000-0003-4920-6328], Zapata-Muñoz, Juan [0000-0003-4747-920X], Villarejo-Zori, Beatriz [0000-0002-5502-4793], Gómez-Sintes, Raquel [0000-0003-2854-6964], Boya, Patricia [0000-0003-3045-951X], Jiménez-Loygorri, Juan Ignacio, Benítez-Fernández, Rocío, Viedma-Poyatos, Álvaro, Zapata-Muñoz, Juan, Villarejo-Zori, Beatriz, Gómez-Sintes, Raquel, Boya, Patricia, Ministerio de Ciencia e Innovación (España), University of Fribourg, Swiss National Science Foundation, Jiménez-Loygorri, Juan Ignacio [0000-0002-3065-9952], Benítez-Fernández, Rocío [0000-0003-3535-4370], Viedma-Poyatos, Álvaro [0000-0003-4920-6328], Zapata-Muñoz, Juan [0000-0003-4747-920X], Villarejo-Zori, Beatriz [0000-0002-5502-4793], Gómez-Sintes, Raquel [0000-0003-2854-6964], Boya, Patricia [0000-0003-3045-951X], Jiménez-Loygorri, Juan Ignacio, Benítez-Fernández, Rocío, Viedma-Poyatos, Álvaro, Zapata-Muñoz, Juan, Villarejo-Zori, Beatriz, Gómez-Sintes, Raquel, and Boya, Patricia

Abstract

Mitochondrial function is key to support metabolism and homeostasis in the retina, an organ that has one of the highest metabolic rates body-wide and is constantly exposed to photooxidative damage and external stressors. Mitophagy is the selective autophagic degradation of mitochondria within lysosomes, and can be triggered by distinct stimuli such as mitochondrial damage or hypoxia. Here, we review the importance of mitophagy in retinal physiology and pathology. In the developing retina, mitophagy is essential for metabolic reprogramming and differentiation of retina ganglion cells (RGCs). In basal conditions, mitophagy acts as a quality control mechanism, maintaining a healthy mitochondrial pool to meet cellular demands. We summarize the different autophagy- and mitophagy-deficient mouse models described in the literature, and discuss the potential role of mitophagy dysregulation in retinal diseases such as glaucoma, diabetic retinopathy, retinitis pigmentosa, and age-related macular degeneration. Finally, we provide an overview of methods used to monitor mitophagy in vitro, ex vivo, and in vivo. This review highlights the important role of mitophagy in sustaining visual function, and its potential as a putative therapeutic target for retinal and other diseases.

Published
2023

4. Cell surface detection of vimentin, ACE2 and SARS-CoV-2 Spike proteins reveals selective colocalization at primary cilia

Author

Consejo Superior de Investigaciones Científicas (España), Ministerio de Ciencia e Innovación (España), Lalioti, Vasiliky S. [0000-0002-4273-6126], González-Jiménez, Patricia [0000-0002-7588-2779], Viedma-Poyatos, Álvaro [0000-0003-4920-6328], Merino, Andrea [0000-0002-1080-3996], Pajares, María A. [0000-0002-4714-9051], Pérez-Sala, Dolores [0000-0003-0600-665X], Lalioti, Vasiliky S., González-Sanz, Silvia, Lois-Bermejo, Irene, González-Jiménez, Patricia, Viedma-Poyatos, Álvaro, Merino, Andrea, Pajares, María A., Pérez-Sala, Dolores, Consejo Superior de Investigaciones Científicas (España), Ministerio de Ciencia e Innovación (España), Lalioti, Vasiliky S. [0000-0002-4273-6126], González-Jiménez, Patricia [0000-0002-7588-2779], Viedma-Poyatos, Álvaro [0000-0003-4920-6328], Merino, Andrea [0000-0002-1080-3996], Pajares, María A. [0000-0002-4714-9051], Pérez-Sala, Dolores [0000-0003-0600-665X], Lalioti, Vasiliky S., González-Sanz, Silvia, Lois-Bermejo, Irene, González-Jiménez, Patricia, Viedma-Poyatos, Álvaro, Merino, Andrea, Pajares, María A., and Pérez-Sala, Dolores

Abstract

The SARS-CoV-2 Spike protein mediates docking of the virus onto cells prior to viral invasion. Several cellular receptors facilitate SARS-CoV-2 Spike docking at the cell surface, of which ACE2 plays a key role in many cell types. The intermediate filament protein vimentin has been reported to be present at the surface of certain cells and act as a co-receptor for several viruses; furthermore, its potential involvement in interactions with Spike proteins has been proposed. Nevertheless, the potential colocalization of vimentin with Spike and its receptors on the cell surface has not been explored. Here we have assessed the binding of Spike protein constructs to several cell types. Incubation of cells with tagged Spike S or Spike S1 subunit led to discrete dotted patterns at the cell surface, which consistently colocalized with endogenous ACE2, but sparsely with a lipid raft marker. Vimentin immunoreactivity mostly appeared as spots or patches unevenly distributed at the surface of diverse cell types. Of note, vimentin could also be detected in extracellular particles and in the cytoplasm underlying areas of compromised plasma membrane. Interestingly, although overall colocalization of vimentin-positive spots with ACE2 or Spike was moderate, a selective enrichment of the three proteins was detected at elongated structures, positive for acetylated tubulin and ARL13B. These structures, consistent with primary cilia, concentrated Spike binding at the top of the cells. Our results suggest that a vimentin-Spike interaction could occur at selective locations of the cell surface, including ciliated structures, which can act as platforms for SARS-CoV-2 docking.

Published
2022

5. The cellular vimentin network undergoes distinct reorganizations in response to diverse electrophiles or mutations of its single cysteine residue

Author

European Commission, Ministerio de Ciencia, Innovación y Universidades (España), Instituto de Salud Carlos III, Duarte, Sofia [0000-0001-5081-6989], Navarro-Carrasco, Elena [0000-0002-1533-8210], Viedma-Poyatos, Álvaro [0000-0003-4920-6328], Pajares, María A. [0000-0002-4714-9051], Pérez-Sala, Dolores [0000-0003-0600-665X], González-Jiménez, Patricia, Duarte, Sofia, Fernández, Alma E., Navarro Carrasco, Elena, González-Sanz, Silvia, Viedma-Poyatos, Álvaro, Pajares, María A., Pérez-Sala, Dolores, European Commission, Ministerio de Ciencia, Innovación y Universidades (España), Instituto de Salud Carlos III, Duarte, Sofia [0000-0001-5081-6989], Navarro-Carrasco, Elena [0000-0002-1533-8210], Viedma-Poyatos, Álvaro [0000-0003-4920-6328], Pajares, María A. [0000-0002-4714-9051], Pérez-Sala, Dolores [0000-0003-0600-665X], González-Jiménez, Patricia, Duarte, Sofia, Fernández, Alma E., Navarro Carrasco, Elena, González-Sanz, Silvia, Viedma-Poyatos, Álvaro, Pajares, María A., and Pérez-Sala, Dolores

Published
2021

6. Protein lipoxidation: basic concepts and emerging roles

Author

Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, European Commission, Ministerio de Ciencia e Innovación (España), Viedma-Poyatos, Álvaro [0000-0003-4920-6328], González-Jiménez, Patricia [0000-0002-7588-2779], Langlois, Ophélie [0000-0002-1844-0966], Spickett, Corinne M. [0000-0003-4054-9279], Pérez-Sala, Dolores [0000-0003-0600-665X], Viedma-Poyatos, Álvaro, González-Jiménez, Patricia, Langlois, Ophélie, Company-Marín, Idoia, Spickett, Corinne M., Pérez-Sala, Dolores, Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, European Commission, Ministerio de Ciencia e Innovación (España), Viedma-Poyatos, Álvaro [0000-0003-4920-6328], González-Jiménez, Patricia [0000-0002-7588-2779], Langlois, Ophélie [0000-0002-1844-0966], Spickett, Corinne M. [0000-0003-4054-9279], Pérez-Sala, Dolores [0000-0003-0600-665X], Viedma-Poyatos, Álvaro, González-Jiménez, Patricia, Langlois, Ophélie, Company-Marín, Idoia, Spickett, Corinne M., and Pérez-Sala, Dolores

Abstract

Protein lipoxidation is a non-enzymatic post-translational modification that consists of the covalent addition of reactive lipid species to proteins. This occurs under basal conditions but increases in situations associated with oxidative stress. Protein targets for lipoxidation include metabolic and signalling enzymes, cytoskeletal proteins, and transcription factors, among others. There is strong evidence for the involvement of protein lipoxidation in disease, including atherosclerosis, neurodegeneration, and cancer. Nevertheless, the involvement of lipoxidation in cellular regulatory mechanisms is less understood. Here we review basic aspects of protein lipoxidation and discuss several features that could support its role in cell signalling, including its selectivity, reversibility, and possibilities for regulation at the levels of the generation and/or detoxification of reactive lipids. Moreover, given the great structural variety of electrophilic lipid species, protein lipoxidation can contribute to the generation of multiple structurally and functionally diverse protein species. Finally, the nature of the lipoxidised proteins and residues provides a frameshift for a complex interplay with other post-translational modifications, including redox and redox-regulated modifications, such as oxidative modifications and phosphorylation, thus strengthening the importance of detailed knowledge of this process.

Published
2021

7. Type III intermediate filaments as targets and effectors of electrophiles and oxidants

Author

Agencia Estatal de Investigación (España), Ministerio de Ciencia e Innovación (España), European Commission, Instituto de Salud Carlos III, Viedma-Poyatos, Álvaro [0000-0003-4920-6328], Pajares, María A. [0000-0002-4714-9051], Pérez-Sala, Dolores [0000-0003-0600-665X], Viedma-Poyatos, Álvaro, Pajares, María A., Pérez-Sala, Dolores, Agencia Estatal de Investigación (España), Ministerio de Ciencia e Innovación (España), European Commission, Instituto de Salud Carlos III, Viedma-Poyatos, Álvaro [0000-0003-4920-6328], Pajares, María A. [0000-0002-4714-9051], Pérez-Sala, Dolores [0000-0003-0600-665X], Viedma-Poyatos, Álvaro, Pajares, María A., and Pérez-Sala, Dolores

Abstract

Intermediate filaments (IFs) play key roles in cell mechanics, signaling and homeostasis. Their assembly and dynamics are finely regulated by posttranslational modifications. The type III IFs, vimentin, desmin, peripherin and glial fibrillary acidic protein (GFAP), are targets for diverse modifications by oxidants and electrophiles, for which their conserved cysteine residue emerges as a hot spot. Pathophysiological examples of these modifications include lipoxidation in cell senescence and rheumatoid arthritis, disulfide formation in cataracts and nitrosation in endothelial shear stress, although some oxidative modifications can also be detected under basal conditions. We previously proposed that cysteine residues of vimentin and GFAP act as sensors for oxidative and electrophilic stress, and as hinges influencing filament assembly. Accumulating evidence indicates that the structurally diverse cysteine modifications, either per se or in combination with other posttranslational modifications,elicit specific functional outcomes inducing distinct assemblies or network rearrangements, including filament stabilization, bundling or fragmentation. Cysteine-deficient mutants are protected from these alterations but show compromised cellular performance in network assembly and expansion, organelle positioning and aggresome formation, revealing the importance of this residue. Therefore, the high susceptibility to modification of the conserved cysteine of type III IFs and its cornerstone position in filament architecture sustains their role in redox sensing and integration of cellular responses. This has deep pathophysiological implications and supports the potential of this residue as a drug target.

Published
2020

8. Vimentin filaments interact with the actin cortex in mitosis allowing normal cell division

Author

European Commission, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Instituto de Salud Carlos III, Duarte, Sofia [0000-0001-5081-6989], Viedma-Poyatos, Álvaro [0000-0003-4920-6328], Navarro-Carrasco, Elena [0000-0002-1533-8210], Martínez, Alma E. [0000-0002-6712-7079], Pajares, María A. [0000-0002-4714-9051], Pérez-Sala, Dolores [0000-0003-0600-665X], Duarte, Sofia, Viedma-Poyatos, Álvaro, Navarro Carrasco, Elena, Martínez, Alma E., Pajares, María A., Pérez-Sala, Dolores, European Commission, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Instituto de Salud Carlos III, Duarte, Sofia [0000-0001-5081-6989], Viedma-Poyatos, Álvaro [0000-0003-4920-6328], Navarro-Carrasco, Elena [0000-0002-1533-8210], Martínez, Alma E. [0000-0002-6712-7079], Pajares, María A. [0000-0002-4714-9051], Pérez-Sala, Dolores [0000-0003-0600-665X], Duarte, Sofia, Viedma-Poyatos, Álvaro, Navarro Carrasco, Elena, Martínez, Alma E., Pajares, María A., and Pérez-Sala, Dolores

Abstract

The vimentin network displays remarkable plasticity to support basic cellular functions and reorganizes during cell division. Here, we show that in several cell types vimentin filaments redistribute to the cell cortex during mitosis, forming a robust framework interwoven with cortical actin and affecting its organization. Importantly, the intrinsically disordered tail domain of vimentin is essential for this redistribution, which allows normal mitotic progression. A tailless vimentin mutant forms curly bundles, which remain entangled with dividing chromosomes leading to mitotic catastrophes or asymmetric partitions. Serial deletions of vimentin tail domain gradually impair cortical association and mitosis progression. Disruption of f-actin, but not of microtubules, causes vimentin bundling near the chromosomes. Pathophysiological stimuli, including HIV-protease and lipoxidation, induce similar alterations. Interestingly, full filament formation is dispensable for cortical association, which also occurs in vimentin particles. These results unveil implications of vimentin dynamics in cell division through its interplay with the actin cortex.

Published
2019

9. Alexander disease GFAP R239C mutant shows increased susceptibility to lipoxidation and elicits mitochondrial dysfunction and oxidative stress

Author

Álvaro Viedma-Poyatos, Patricia González-Jiménez, María A. Pajares, Dolores Pérez-Sala, Agencia Estatal de Investigación (España), Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, European Commission, Viedma-Poyatos, Álvaro [0000-0003-4920-6328], González-Jiménez, Patricia [0000-0002-7588-2779], Pajares, María A. [0000-0002-4714-9051], Pérez-Sala, Dolores [0000-0003-0600-665X], Viedma-Poyatos, Álvaro, González-Jiménez, Patricia, Pajares, María A., and Pérez-Sala, Dolores

Subjects
GFAP aggregation, AxD cellular model, Organic Chemistry, Clinical Biochemistry, Oxidative damage, Neurodegeneration, Mitochondrial dysfunction, Biochemistry, Protein lipoxidation
Abstract

18 p.-10 fig., Alexander disease is a fatal neurological disorder caused by mutations in the intermediate filament protein Glial Fibrillary Acidic Protein (GFAP), which is key for astrocyte homeostasis. These mutations cause GFAP aggregation, astrocyte dysfunction and neurodegeneration. Remarkably, most of the known GFAP mutations imply a change by more nucleophilic amino acids, mainly cysteine or histidine, which are more susceptible to oxidation and lipoxidation. Therefore, we hypothesized that a higher susceptibility of Alexander disease GFAP mutants to oxidative or electrophilic damage, which frequently occurs during neurodegeneration, could contribute to disease pathogenesis. To address this point, we have expressed GFP-GFAP wild type or the harmful Alexander disease GFP-GFAP R239C mutant in astrocytic cells. Interestingly, GFAP R239C appears more oxidized than the wild type under control conditions, as indicated both by its lower cysteine residue accessibility and increased presence of disulfide-bonded oligomers. Moreover, GFP-GFAP R239C undergoes lipoxidation to a higher extent than GFAP wild type upon treatment with the electrophilic mediator 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2). Importantly, GFAP R239C filament organization is altered in untreated cells and is earlier and more severely disrupted than GFAP wild type upon exposure to oxidants (diamide, H2O2) or electrophiles (4-hydroxynonenal, 15d-PGJ2), which exacerbate GFAP R239C aggregation. Furthermore, H2O2 causes reversible alterations in GFAP wild type, but irreversible damage in GFAP R239C expressing cells. Finally, we show that GFAP R239C expression induces a more oxidized cellular status, with decreased free thiol content and increased mitochondrial superoxide generation. In addition, mitochondria show decreased mass, increased colocalization with GFAP and altered morphology. Notably, a GFP-GFAP R239H mutant recapitulates R239C-elicited alterations whereas an R239G mutant induces a milder phenotype. Together, our results outline a deleterious cycle involving altered GFAP R239C organization, mitochondrial dysfunction, oxidative stress, and further GFAP R239C protein damage and network disruption, which could contribute to astrocyte derangement in Alexander disease., This work was supported by Agencia Estatal de Investigación, MICINN/ERDF (grants SAF2015-68590R and RTI2018-097624-B-I00), and ISCIII/ERDF (RETIC ARADYAL RD16/0006/0021), Spain. AVP and PGJ were supported by FPI grants BES-2016-076965 and PRE2019-088194 from MICINN/ERDF, respectively (ERDF, co-funded by the European Regional Development Fund).

Published
2022

10. Cell surface detection of vimentin, ACE2 and SARS-CoV-2 Spike proteins reveals selective colocalization at primary cilia

Author

Vasiliki Lalioti, Silvia González-Sanz, Irene Lois-Bermejo, Patricia González-Jiménez, Álvaro Viedma-Poyatos, Andrea Merino, María A. Pajares, Dolores Pérez-Sala, Consejo Superior de Investigaciones Científicas (España), Ministerio de Ciencia e Innovación (España), Lalioti, Vasiliky S., González-Jiménez, Patricia, Viedma-Poyatos, Álvaro, Merino, Andrea, Pajares, María A., Pérez-Sala, Dolores, Lalioti, Vasiliky S. [0000-0002-4273-6126], González-Jiménez, Patricia [0000-0002-7588-2779], Viedma-Poyatos, Álvaro [0000-0003-4920-6328], Merino, Andrea [0000-0002-1080-3996], Pajares, María A. [0000-0002-4714-9051], and Pérez-Sala, Dolores [0000-0003-0600-665X]

Subjects
Multidisciplinary, Membrane Microdomains, SARS-CoV-2, Spike Glycoprotein, Coronavirus, COVID-19, Humans, Vimentin, macromolecular substances, Angiotensin-Converting Enzyme 2, Cilia, Peptidyl-Dipeptidase A
Abstract

19 p.-9 fig., The SARS-CoV-2 Spike protein mediates docking of the virus onto cells prior to viral invasion. Several cellular receptors facilitate SARS-CoV-2 Spike docking at the cell surface, of which ACE2 plays a key role in many cell types. The intermediate filament protein vimentin has been reported to be present at the surface of certain cells and act as a co-receptor for several viruses; furthermore, its potential involvement in interactions with Spike proteins has been proposed. Nevertheless, the potential colocalization of vimentin with Spike and its receptors on the cell surface has not been explored. Here we have assessed the binding of Spike protein constructs to several cell types. Incubation of cells with tagged Spike S or Spike S1 subunit led to discrete dotted patterns at the cell surface, which consistently colocalized with endogenous ACE2, but sparsely with a lipid raft marker. Vimentin immunoreactivity mostly appeared as spots or patches unevenly distributed at the surface of diverse cell types. Of note, vimentin could also be detected in extracellular particles and in the cytoplasm underlying areas of compromised plasma membrane. Interestingly, although overall colocalization of vimentin-positive spots with ACE2 or Spike was moderate, a selective enrichment of the three proteins was detected at elongated structures, positive for acetylated tubulin and ARL13B. These structures, consistent with primary cilia, concentrated Spike binding at the top of the cells. Our results suggest that a vimentin-Spike interaction could occur at selective locations of the cell surface, including ciliated structures, which can act as platforms for SARS-CoV-2 docking., This work was supported by grants from Consejo Superior de Investigaciones Científicas, CSIC PTI Global Health (PIE 202020E223/CSIC-COV19-100), RTI2018-097624-B-I00 from Ministerio de Ciencia e Innovación, Micinn (Agencia Estatal de Investigación), Spain, and European Regional Development Fund, EDRF (. Á.V.P. and P.G.J. are the recipients of predoctoral contracts BES-2016-076965 and PRE2019-088194, respectively, from Ministerio de Ciencia e Innovación, Spain.

Published
2021

11. The cellular vimentin network undergoes distinct reorganizations in response to diverse electrophiles or mutations of its single cysteine residue

Author

Sofia Duarte, Elena Navarro-Carrasco, María A. Pajares, Alma E. Fernández, Álvaro Viedma-Poyatos, Silvia González-Sanz, Patricia González-Jiménez, Dolores Pérez-Sala, European Commission, Ministerio de Ciencia, Innovación y Universidades (España), Instituto de Salud Carlos III, Duarte, Sofia, Navarro-Carrasco, Elena, Viedma-Poyatos, Álvaro, Pajares, María A., Pérez-Sala, Dolores, Duarte, Sofia [0000-0001-5081-6989], Navarro-Carrasco, Elena [0000-0002-1533-8210], Viedma-Poyatos, Álvaro [0000-0003-4920-6328], Pajares, María A. [0000-0002-4714-9051], and Pérez-Sala, Dolores [0000-0003-0600-665X]

Subjects
0303 health sciences, biology, Chemistry, Stereochemistry, Vimentin, Biochemistry, 3. Good health, 03 medical and health sciences, Residue (chemistry), 0302 clinical medicine, Physiology (medical), Electrophile, biology.protein, 030217 neurology & neurosurgery, 030304 developmental biology, Cysteine
Abstract

1 p. (Abtracts of SFRR-International 2021 Virtual Meeting), H2020 grant-675132, “Masstrplan”; RTI2018-097624-B-100 (MCINN, ERDF); RETIC-Aradyal RD16/0006/0021 (ISCIII-ERDF); MICINN BES-2016-076965 (AVP), PRE2019-088194 (PG).

Published
2021

12. Protein Lipoxidation: Basic Concepts and Emerging Roles

Author

Corinne M. Spickett, Patricia González-Jiménez, Dolores Pérez-Sala, Ophélie Langlois, Álvaro Viedma-Poyatos, Idoia Company-Marín, Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, European Commission, Ministerio de Ciencia e Innovación (España), Viedma-Poyatos, Álvaro [0000-0003-4920-6328], González-Jiménez, Patricia [0000-0002-7588-2779], Langlois, Ophélie [0000-0002-1844-0966], Spickett, Corinne M. [0000-0003-4054-9279], Pérez-Sala, Dolores [0000-0003-0600-665X], Viedma-Poyatos, Álvaro, González-Jiménez, Patricia, Langlois, Ophélie, Spickett, Corinne M., and Pérez-Sala, Dolores

Subjects
0301 basic medicine, Cell signaling, Physiology, Clinical Biochemistry, electrophilic lipids, Review, Oxidative phosphorylation, lipoxidation, medicine.disease_cause, Biochemistry, 03 medical and health sciences, post-translational modifications, medicine, oxidative stress, Selectivity, Cytoskeleton, Molecular Biology, Transcription factor, chemistry.chemical_classification, Electrophilic lipids, 030102 biochemistry & molecular biology, Chemistry, lcsh:RM1-950, Neurodegeneration, selectivity, cell signalling, regulation, Cell Biology, medicine.disease, Cell biology, Lipoxidation, lcsh:Therapeutics. Pharmacology, 030104 developmental biology, Enzyme, Oxidative stress, Phosphorylation, Cell signalling, Regulation, Post-translational modifications
Abstract

25 p.-3 fig.-3 tab., Protein lipoxidation is a non-enzymatic post-translational modification that consists of the covalent addition of reactive lipid species to proteins. This occurs under basal conditions but increases in situations associated with oxidative stress. Protein targets for lipoxidation include metabolic and signalling enzymes, cytoskeletal proteins, and transcription factors, among others. There is strong evidence for the involvement of protein lipoxidation in disease, including atherosclerosis, neurodegeneration, and cancer. Nevertheless, the involvement of lipoxidation in cellular regulatory mechanisms is less understood. Here we review basic aspects of protein lipoxidation and discuss several features that could support its role in cell signalling, including its selectivity, reversibility, and possibilities for regulation at the levels of the generation and/or detoxification of reactive lipids. Moreover, given the great structural variety of electrophilic lipid species, protein lipoxidation can contribute to the generation of multiple structurally and functionally diverse protein species. Finally, the nature of the lipoxidised proteins and residues provides a frameshift for a complex interplay with other post-translational modifications, including redox and redox-regulated modifications, such as oxidative modifications and phosphorylation, thus strengthening the importance of detailed knowledge of this process., Work at DPS laboratory is supported by RTI2018-097624-B-I00 from Agencia Estatal de Investigación, MICINN/ERDF, and RETIC ARADYAL RD16/0006/0021 from ISCIII/ERDF, Spain Work at CMS laboratory (including I.C.M. and O.L.) is supported by funding from the European Union’s Horizon 2020 research and innovation programme under Marie Sklodowska-Curie grant agreement No 847419 (MemTrain). Á.V.P. and P.G.J. are the recipients of predoctoral contracts BES-2016-076965 and PRE2019-088194, respectively, from MICINN, Spain.

Published
2021

13. Type III intermediate filaments as targets and effectors of electrophiles and oxidants

Author

Dolores Pérez-Sala, María A. Pajares, Álvaro Viedma-Poyatos, Agencia Estatal de Investigación (España), Ministerio de Ciencia e Innovación (España), European Commission, Instituto de Salud Carlos III, Viedma-Poyatos, Álvaro [0000-0003-4920-6328], Pajares, María A. [0000-0002-4714-9051], Pérez-Sala, Dolores [0000-0003-0600-665X], Viedma-Poyatos, Álvaro, Pajares, María A., and Pérez-Sala, Dolores

Subjects
0301 basic medicine, Redox sensing, Clinical Biochemistry, Intermediate Filaments, Vimentin, macromolecular substances, Review Article, Biochemistry, Desmin, Protein filament, 03 medical and health sciences, 0302 clinical medicine, Glial Fibrillary Acidic Protein, Intermediate filament, lcsh:QH301-705.5, Cytoskeleton, lcsh:R5-920, Glial fibrillary acidic protein, biology, Chemistry, GFAP, Organic Chemistry, Peripherin, Oxidants, Cell biology, Lipoxidation, 030104 developmental biology, Aggresome, lcsh:Biology (General), biology.protein, Cysteine oxidative modifications, lcsh:Medicine (General), 030217 neurology & neurosurgery, Cysteine
Abstract

16 p.-5 fig., Intermediate filaments (IFs) play key roles in cell mechanics, signaling and homeostasis. Their assembly and dynamics are finely regulated by posttranslational modifications. The type III IFs, vimentin, desmin, peripherin and glial fibrillary acidic protein (GFAP), are targets for diverse modifications by oxidants and electrophiles, for which their conserved cysteine residue emerges as a hot spot. Pathophysiological examples of these modifications include lipoxidation in cell senescence and rheumatoid arthritis, disulfide formation in cataracts and nitrosation in endothelial shear stress, although some oxidative modifications can also be detected under basal conditions. We previously proposed that cysteine residues of vimentin and GFAP act as sensors for oxidative and electrophilic stress, and as hinges influencing filament assembly. Accumulating evidence indicates that the structurally diverse cysteine modifications, either per se or in combination with other posttranslational modifications,elicit specific functional outcomes inducing distinct assemblies or network rearrangements, including filament stabilization, bundling or fragmentation. Cysteine-deficient mutants are protected from these alterations but show compromised cellular performance in network assembly and expansion, organelle positioning and aggresome formation, revealing the importance of this residue. Therefore, the high susceptibility to modification of the conserved cysteine of type III IFs and its cornerstone position in filament architecture sustains their role in redox sensing and integration of cellular responses. This has deep pathophysiological implications and supports the potential of this residue as a drug target., This work was supported by Grants from Agencia Estatal de Investigación, Ministerio de Ciencia e Innovación (MCI, Spain) and European Regional Development Fund, RTI2018-097624-B-I00,Instituto de Salud Carlos III (Spain) RETIC AraDyal RD16/0006/0021,and CSIC PTI Global Health (PIE202020E223/CSIC-COV19-100). AV-P is supported by the FPI program from MCI, reference BES-2016-076965.

Published
2020

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