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TRIM65 E3 ligase targets VCAM-1 degradation to limit LPS-induced lung inflammation
- Source :
- Journal of Molecular Cell Biology
- Publication Year :
- 2019
- Publisher :
- Oxford University Press, 2019.
-
Abstract
- Although the adhesion molecules-mediated leukocyte adherence and infiltration into tissues is an important step of inflammation, the post-translational regulation of these proteins on the endothelial cells is poorly understood. Here, we report that TRIM65, an ubiquitin E3 ligase of tripartite protein family, selectively targets vascular cell adhesion molecule 1 (VCAM-1) and promotes its ubiquitination and degradation, by which it critically controls the duration and magnitude of sepsis-induced pulmonary inflammation. TRIM65 is constitutively expressed in human vascular endothelial cells. During TNFα-induced endothelial activation, the protein levels of TRIM65 and VCAM-1 are inversely correlated. Expression of wild-type TRIM65, but not expression of a TRIM65 mutant that lacks E3 ubiquitin ligase function in endothelial cells, promotes VCAM-1 ubiquitination and degradation, whereas small interference RNA-mediated knockdown of TRIM65 attenuates VCAM-1 protein degradation. Further experiments show that TRIM65 directly interacts with VCAM-1 protein and directs its polyubiquitination, by which TRIM65 controls monocyte adherence and infiltration into tissues during inflammation. Importantly, TRIM65-deficient mice are more sensitive to lipopolysaccharide-induced death, due to sustained and severe pulmonary inflammation. Taken together, our studies suggest that TRIM65-mediated degradation of VCAM-1 represents a potential mechanism that controls the duration and magnitude of inflammation.
- Subjects :
- Lipopolysaccharides
Endothelium
Ubiquitin-Protein Ligases
Vascular Cell Adhesion Molecule-1
Inflammation
endothelial activation
Protein degradation
Article
Monocytes
Endothelial activation
Tripartite Motif Proteins
chemistry.chemical_compound
Mice
Ubiquitin
Genetics
medicine
Animals
Humans
VCAM-1
Molecular Biology
biology
Cell adhesion molecule
lung inflammation
Ubiquitination
Endothelial Cells
Cell Biology
General Medicine
Pneumonia
Cell biology
Ubiquitin ligase
Disease Models, Animal
medicine.anatomical_structure
chemistry
Gene Expression Regulation
Proteolysis
biology.protein
Disease Susceptibility
medicine.symptom
TRIM65
Gene Deletion
Protein Binding
Subjects
Details
- Language :
- English
- ISSN :
- 17594685 and 16742788
- Volume :
- 12
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Journal of Molecular Cell Biology
- Accession number :
- edsair.doi.dedup.....78ab32744bb7d386aeaf90131226a5c3