한빛사논문
- 조회2,268
Abstract
Qiming Liang1,4,*, Zhifei Luo2,3, Jianxiong Zeng1, Weiqiang Chen1, Suan-Sin Foo1, Shin-Ae Lee1, Jianning Ge1, Su Wang5,6,7, Steven A. Goldman5,6,7, Berislav V. Zlokovic2,3, Zhen Zhao2,3,*, Jae U. Jung1,8,*
1 Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
2 Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
3 Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
4 Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
5 Center for Translational Neuromedicine, University of Rochester, Rochester, NY 14642, USA
6 Department of Neurology, University of Rochester, Rochester, NY 14642, USA
7 Faculty of Health and Medical Sciences, University of Copenhagen, 1165 Copenhagen, Denmark
8Lead Contact
*Corresponding authors
Summary
The current widespread outbreak of Zika virus (ZIKV) infection has been linked to severe clinical birth defects, particularly microcephaly, warranting urgent study of the molecular mechanisms underlying ZIKV pathogenesis. Akt-mTOR signaling is one of the key cellular pathways essential for brain development and autophagy regulation. Here, we show that ZIKV infection of human fetal neural stem cells (fNSCs) causes inhibition of the Akt-mTOR pathway, leading to defective neurogenesis and aberrant activation of autophagy. By screening the three structural proteins and seven nonstructural proteins present in ZIKV, we found that two, NS4A and NS4B, cooperatively suppress the Akt-mTOR pathway and lead to cellular dysregulation. Corresponding proteins from the closely related dengue virus do not have the same effect on neurogenesis. Thus, our study highlights ZIKV NS4A and NS4B as candidate determinants of viral pathogenesis and identifies a mechanism of action for their effects, suggesting potential targets for anti-ZIKV therapeutic intervention.
논문정보
- Research article
- 2016년 08월 (BRIC 등록일 2016-08-17)
- 국외 연구진
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