On the mechanism of calcium‐dependent activation of NADPH oxidase 5 (NOX5)

Fañanás, Elisa Millana; Todesca, Sofia; Sicorello, Alessandro; Pompach, Petr; Magnani, Francesca; Pastore, Annalisa; Mattevi, Andrea

doi:10.1111/febs.15160

Cited by 31 publications

(23 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Its regulation is different to other NOX homologues since it does not present cytoplasmic subunits that could modulate its catalytic activity [ 13 ]. NOX5 contains “EF-hand” domains that undergo conformational changes in the presence of Ca 2+ , promoting interaction with the catalytic domain and inducing superoxide production [ 14 ]. NOX5 presents five different isoforms associated to alternative splicing [ 11 ], and NOX5-β is the most relevant one in vessels [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

NADPH Oxidase 5 Induces Changes in the Unfolded Protein Response in Human Aortic Endothelial Cells and in Endothelial-Specific Knock-in Mice

et al. 2021

View full text Add to dashboard Cite

Oxidative stress constitutes a key molecular mechanism in the development of cardiovascular diseases. A potential relationship between reactive oxygen species (ROS) driven by the NADPH oxidase family (NOX) and the unfolded protein response (UPR) has been postulated. Nevertheless, there is a lack of information about the crosstalk between NOX5 homologue and the UPR in a cardiovascular context. The main aim was to analyze NOX5-mediated ROS effects in the UPR and its importance in cardiovascular diseases. To this effect, we used an adenoviral NOX5-β overexpression model in human aortic endothelial cells (HAEC) and a conditional endothelial NOX5 knock-in mouse. Using expression arrays, we investigated NOX5-induced genomic changes in HAEC. Compared with the control HAEC, 298 genes were differentially expressed. Gene ontology analysis revealed the activation of numerous cellular routes, the most relevant being the UPR pathway. Using real-time PCR and Western Blot experiments, we confirmed that NOX5 overexpression induced changes in the expression of the UPR components, which were associated with increased apoptosis. Moreover, in endothelial-specific NOX5 knock-in mice, we found changes in the expression of the UPR components genes. In these mice, myocardial infarction was performed by permanent coronary artery ligation; however, NOX5 expression was not associated with differences in the UPR components mRNA levels. In these animals, we found significant associations between the UPR components gene expression and echocardiographic parameters. Our data support the idea that NOX5-derived ROS may modulate the UPR pathway in endothelial cells, which might play a relevant role in cardiac physiology.

show abstract

Section: Introductionmentioning

confidence: 99%

NADPH Oxidase 5 Induces Changes in the Unfolded Protein Response in Human Aortic Endothelial Cells and in Endothelial-Specific Knock-in Mice

et al. 2021

View full text Add to dashboard Cite

show abstract

“…A broad range of binding modes have been found for CaM in complex with target proteins, revealing considerable structural flexibility of CaM in target engagement ( Tidow and Nissen, 2013 ). The here observed binding mode of CaM in an extended conformation with one peptide bound to each lobe is relatively unique and has only been seen in one previous case, i.e., CaM in complex with two identical peptides from a NADPH oxidase (PDB ID: 6SZ5 ) ( Fañanás et al., 2020 ). More commonly, crystal structures that show CaM in an extended conformation contain only one bound peptide to the C-lobe of CaM, as exemplified by a peptide from the voltage-gated Na + channel NaV1.5 (PDB ID: 4DJC ) ( Sarhan et al., 2012 ) and reviewed by Tidow and Nissen (2013) .…”

Section: Discussionmentioning

confidence: 63%

“…Some other extended CaM crystal structures display a similar crystal contact interface, e.g. in CaM in complex with peptides from the NADPH oxidase 5 (PDB ID: 6SZ5 ) ( Fañanás et al., 2020 ), whereas the distance of >4 Å between the carboxyl oxygen of Asp119 and Ca 2+ is too large for a Ca 2+ -coordination in some cases (e.g. PDB ID: 6MUE and 1EXT ).…”

Section: Resultsmentioning

confidence: 99%

Calmodulin complexes with brain and muscle creatine kinase peptides

Sprenger

Trifan

Patel

et al. 2021

Current Research in Structural Biology

View full text Add to dashboard Cite

Calmodulin (CaM) is a ubiquitous Ca 2+ sensing protein that binds to and modulates numerous target proteins and enzymes during cellular signaling processes. A large number of CaM-target complexes have been identified and structurally characterized, revealing a wide diversity of CaM-binding modes. A newly identified target is creatine kinase (CK), a central enzyme in cellular energy homeostasis. This study reports two high-resolution X-ray structures, determined to 1.24 Å and 1.43 Å resolution, of calmodulin in complex with peptides from human brain and muscle CK, respectively. Both complexes adopt a rare extended binding mode with an observed stoichiometry of 1:2 CaM:peptide, confirmed by isothermal titration calorimetry, suggesting that each CaM domain independently binds one CK peptide in a Ca 2+ -depended manner. While the overall binding mode is similar between the structures with muscle or brain-type CK peptides, the most significant difference is the opposite binding orientation of the peptides in the N-terminal domain. This may extrapolate into distinct binding modes and regulation of the full-length CK isoforms. The structural insights gained in this study strengthen the link between cellular energy homeostasis and Ca 2+ -mediated cell signaling and may shed light on ways by which cells can ‘fine tune’ their energy levels to match the spatial and temporal demands.

show abstract

“…Furthermore, NOX5 is widely expressed and active among the vasculature [ 21 ], and it is known to be a professional producer of superoxide anion [ 34 ]. Although NOX5 has been associated with several chronic and acute pathologies, its relevance in the neuropathology remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Expression of Endothelial NOX5 Alters the Integrity of the Blood-Brain Barrier and Causes Loss of Memory in Aging Mice

et al. 2021

View full text Add to dashboard Cite

Blood-Brain barrier (BBB) disruption is a hallmark of central nervous system (CNS) dysfunction, and oxidative stress is one of the molecular mechanisms that may underlie this process. NADPH oxidases (NOX) are involved in oxidative stress-mediated vascular dysfunction and participate in the pathophysiology of its target organs. The NADPH oxidase 5 (NOX5) isoform is absent in rodents, and although little is known about the role it may play in disrupting the BBB, it has recently been implicated in experimental stroke. Our aim was to investigate the role of NADPH oxidase 5 (NOX5) in promoting vascular alterations and to identify its impact on the cognitive status of aged mice. No differences were detected in the arterial blood pressure or body weight between knock-in mice expressing endothelial NOX5 and the control mice. The Morris water maze test showed memory impairments in the aged knock-in mice expressing NOX5 compared with their control littermates. For assessing the BBB integrity, we studied the protein expression of two tight junction (TJ) proteins: Zonula occludens-1 (ZO-1) and occludin. Compared to the control animals, Aged NOX5 mice exhibited reduced levels of both proteins, demonstrating an alteration of the BBB integrity. Our data indicate that vascular NOX5 may favor behavioral changes with aging through oxidative stress-mediated BBB breakdown.

show abstract

On the mechanism of calcium‐dependent activation of NADPH oxidase 5 (NOX5)

Cited by 31 publications

References 42 publications

NADPH Oxidase 5 Induces Changes in the Unfolded Protein Response in Human Aortic Endothelial Cells and in Endothelial-Specific Knock-in Mice

NADPH Oxidase 5 Induces Changes in the Unfolded Protein Response in Human Aortic Endothelial Cells and in Endothelial-Specific Knock-in Mice

Calmodulin complexes with brain and muscle creatine kinase peptides

Expression of Endothelial NOX5 Alters the Integrity of the Blood-Brain Barrier and Causes Loss of Memory in Aging Mice

Contact Info

Product

Resources

About