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SOCS3-microtubule interaction via CLIP-170 and CLASP2 is critical for modulation of endothelial inflammation and lung injury.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2021 Jan-Jun; Vol. 296, pp. 100239. Date of Electronic Publication: 2021 Jan 09. - Publication Year :
- 2021
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Abstract
- Proinflammatory cytokines such as IL-6 induce endothelial cell (EC) barrier disruption and trigger an inflammatory response in part by activating the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway. The protein suppressor of cytokine signaling-3 (SOCS3) is a negative regulator of JAK-STAT, but its role in modulation of lung EC barrier dysfunction caused by bacterial pathogens has not been investigated. Using human lung ECs and EC-specific SOCS3 knockout mice, we tested the hypothesis that SOCS3 confers microtubule (MT)-mediated protection against endothelial dysfunction. SOCS3 knockdown in cultured ECs or EC-specific SOCS3 knockout in mice resulted in exacerbated lung injury characterized by increased permeability and inflammation in response to IL-6 or heat-killed Staphylococcus aureus (HKSA). Ectopic expression of SOCS3 attenuated HKSA-induced EC dysfunction, and this effect required assembled MTs. SOCS3 was enriched in the MT fractions, and treatment with HKSA disrupted SOCS3-MT association. We discovered that-in addition to its known partners gp130 and JAK2-SOCS3 interacts with MT plus-end binding proteins CLIP-170 and CLASP2 via its N-terminal domain. The resulting SOCS3-CLIP-170/CLASP2 complex was essential for maximal SOCS3 anti-inflammatory effects. Both IL-6 and HKSA promoted MT disassembly and disrupted SOCS3 interaction with CLIP-170 and CLASP2. Moreover, knockdown of CLIP-170 or CLASP2 impaired SOCS3-JAK2 interaction and abolished the anti-inflammatory effects of SOCS3. Together, these findings demonstrate for the first time an interaction between SOCS3 and CLIP-170/CLASP2 and reveal that this interaction is essential to the protective effects of SOCS3 in lung endothelium.<br />Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.<br /> (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Acute Lung Injury genetics
Acute Lung Injury microbiology
Acute Lung Injury pathology
Animals
Cytoskeleton genetics
Endothelial Cells
Endothelium, Vascular metabolism
Endothelium, Vascular microbiology
Endothelium, Vascular pathology
Humans
Inflammation metabolism
Inflammation microbiology
Inflammation pathology
Intercellular Junctions genetics
Interleukin-6 genetics
Lung Injury metabolism
Lung Injury microbiology
Lung Injury pathology
Mice
Mice, Knockout
Permeability
Staphylococcus aureus pathogenicity
Inflammation genetics
Lung Injury genetics
Microtubule-Associated Proteins genetics
Neoplasm Proteins genetics
Suppressor of Cytokine Signaling 3 Protein genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 296
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 33372035
- Full Text :
- https://doi.org/10.1074/jbc.RA120.014232