2. Academic Validation
  3. HIV-1 exposure promotes PKG1-mediated phosphorylation and degradation of stathmin to increase epithelial barrier permeability

HIV-1 exposure promotes PKG1-mediated phosphorylation and degradation of stathmin to increase epithelial barrier permeability

  • J Biol Chem. 2021 Jan-Jun;296:100644. doi: 10.1016/j.jbc.2021.100644.
Wei Xie 1,  Mingzhen Chen 1,  Zhaodong Zhai 1,  Hongjie Li 1,  Ting Song 1,  Yigao Zhu 1,  Dan Dong 1,  Peng Zhou 1,  Liangwei Duan 2,  You Zhang 2,  Dengwen Li 2,  Xinqi Liu 2,  Jun Zhou 3,  Min Liu 4
Affiliations

Affiliations

  • 1 Shandong Provincial Key Laboratory of Animal Resistance Biology, Collaborative Innovation Center of Cell Biology in Universities of Shandong, Institute of Biomedical Sciences, College of Life Sciences, Shandong Normal University, Jinan, Shandong, China.
  • 2 State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, China.
  • 3 Shandong Provincial Key Laboratory of Animal Resistance Biology, Collaborative Innovation Center of Cell Biology in Universities of Shandong, Institute of Biomedical Sciences, College of Life Sciences, Shandong Normal University, Jinan, Shandong, China; State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, China. Electronic address: junzhou@sdnu.edu.cn.
  • 4 Shandong Provincial Key Laboratory of Animal Resistance Biology, Collaborative Innovation Center of Cell Biology in Universities of Shandong, Institute of Biomedical Sciences, College of Life Sciences, Shandong Normal University, Jinan, Shandong, China. Electronic address: minliu@sdnu.edu.cn.
PMID: 33839152 DOI: 10.1016/j.jbc.2021.100644
Abstract

Exposure of mucosal epithelial cells to the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein gp120 is known to disrupt epithelial cell junctions by impairing stathmin-mediated microtubule depolymerization. However, the pathological significance of this process and its underlying molecular mechanism remain unclear. Here we show that treatment of epithelial cells with pseudotyped HIV-1 viral particles or recombinant gp120 protein results in the activation of protein kinase G 1 (PKG1). Examination of epithelial cells by immunofluorescence microscopy reveals that PKG1 activation mediates the epithelial barrier damage upon HIV-1 exposure. Immunoprecipitation experiments show that PKG1 interacts with stathmin and phosphorylates stathmin at serine 63 in the presence of gp120. Immunoprecipitation and immunofluorescence microscopy further demonstrate that PKG1-mediated phosphorylation of stathmin promotes its autophagic degradation by enhancing the interaction between stathmin and the Autophagy adaptor protein p62. Collectively, these results suggest that HIV-1 exposure exploits the PKG1/stathmin axis to affect the microtubule Cytoskeleton and thereby perturbs epithelial cell junctions. Our findings reveal a novel molecular mechanism by which exposure to HIV-1 increases epithelial permeability, which has implications for the development of effective strategies to prevent mucosal HIV-1 transmission.

Keywords

cell junction; human immunodeficiency virus (HIV); microtubule; phosphorylation; protein kinase G (PKG); stathmin.

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