Phosphorylation of Claudin-5 and Occludin by Rho Kinase in Brain Endothelial Cells
Open accessAbstract
Critical to the proper maintenance of blood-brain-barrier (BBB) integrity are the endothelial tight junctions (TJs). Posttranslational modifications of essential endothelial TJ proteins, occludin and claudin-5, contribute and possibly disrupt BBB integrity. Our previous work has shown that Rho kinase (RhoK) activation mediates occludin and claudin-5 phosphorylation resulting in diminished barrier tightness and enhanced monocyte migration across BBB in the setting of human immunodeficiency virus-1 encephalitis (HIVE). To determine whether RhoK can directly phosphorylate TJ proteins, we examined phosphorylation of cytoplasmic domains of recombinant claudin-5 and occludin by RhoK. We found that RhoK predominately phosphorylated two sites on occludin (T382 and S507) and one site on claudin-5 (T207). Specific anti-phosphopeptide antibodies were developed for these sites, allowing the detection of phosphorylated occludin at T382 and S507, and claudin-5 at T207 from full-length recombinant occludin and claudin-5 transiently expressed in COS-7 cells and mouse brain microvascular endothelial cells. Finally, these phosphospecific antibodies demonstrated enhanced staining of brain endothelial cells in the mouse model for HIVE and human HIVE brains featuring mononuclear cell infiltration across disrupted BBB. Our results demonstrated the direct phosphorylation of occludin and claudin-5 by RhoK at specific sites, which was increased in encephalitic brain tissue. These antibodies could be useful reagents for monitoring BBB dysfunction in vivo.
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In HIV-1-associated dementia or HIV encephalitis, post mortem brain tissue studies report microvascular degeneration and blood-brain barrier breakdown including reduced pericyte coverage, reduced and disrupted tight junctions, capillary basement membrane changes, perivascular macrophage infiltration, and reduced brain endothelial ABCB1 (P-gp) expression.
“Post mortem brain tissue studies in HAD or HIV encephalitis report microvascular degeneration and BBB breakdown including reduced pericyte coverage (439), reduced and disrupted TJs (471, 664), capillary basement membrane changes (471), perivascular macrophage infiltration (471), and reduced brain endothelial ABCB1 (P-gp) expression (346).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [664]
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- Authors
- Yamamoto, M., Ramirez, S. H., Sato, S., Kiyota, T., Cerny, R. L., Kaibuchi, K., Persidsky, Y., & Ikezu, T.
- Affiliations
- University of Nebraska Medical Center (US)
- University of Nebraska–Lincoln (US)
- Nagoya University (JP)
- Corresponding author
- Persidsky, Yuri
- Ikezu, Tsuneya
- ORCID
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2008-02
- Volume
- 172
- Issue
- 2
- Pages
- 521-533
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC2312373
- OpenAlex
- W2164118729
- Cited by
- 241
- References
- 52
- Citations by year
- 2026: 12 · 2025: 3 · 2024: 12 · 2023: 12 · 2022: 11 · 2021: 12 · 2020: 16 · 2019: 9 · 2018: 13 · 2017: 12 · 2016: 16 · 2015: 13 · 2014: 16 · 2013: 16 · 2012: 19
- FWCI
- 10.78
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- American Journal Of Pathology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Lincoln (University of Nebraska) (submittedVersion)
- Funders
- National Institutes of Health
- National Institute on Alcohol Abuse and Alcoholism (R37AA015913, R01AA015913)
- National Institute of Mental Health (R01MH072539, R01MH065151, R01-MH65151)
- National Institute of Neurological Disorders and Stroke (P01NS043985)
- National Center for Research Resources (P20 RR-15635, P20RR015635)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
- Keywords
- Rho kinase, claudin-5, occludin, protein phosphorylation, tight junctions, blood-brain barrier integrity, brain microvascular endothelial cells, HIV-1 encephalitis, monocyte migration, phospho-specific antibodies, mononuclear cell infiltration
- MeSH terms
- Amino Acid Sequence, Animals, Antibodies, Blood-Brain Barrier, Brain, Encephalitis, Humans, Membrane Proteins, Molecular Sequence Data, Phosphorylation, Recombinant Fusion Proteins, Transfection, Blotting, Western, HIV-1, HIV Infections, Tight Junctions, Endothelial Cells, Immunoprecipitation, Mice, G-Protein-Coupled Receptor Kinase 1, Claudin-5, Occludin
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