SOCS3 microtubule interaction via CLIP-170 and CLASP2 is critical for modulation of endothelial inflammation and lung injury

Pratap Karki, Yunbo Ke, Chen Ou Zhang, Yue Li, Yufeng Tian, Sophia Son, Akihiko Yoshimura, Kozo Kaibuchi, Konstantin G. Birukov, Anna A. Birukova

Research output: Contribution to journalArticlepeer-review

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 ECspecific 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 HKSAinduced 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 antiinflammatory 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.

Original languageEnglish
Article number100239
JournalJournal of Biological Chemistry
Volume296
DOIs
Publication statusPublished - 01-01-2021
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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