Zika Virus Protease Cleavage of Host Protein Septin-2 Mediates Mitotic Defects in Neural Progenitors

Hongda Li; Laura Saucedo-Cuevas; Ling Yuan; Danica Ross; Anide Johansen; Daniel Sands; Valentina Stanley; Alicia Guemez-Gamboa; Anne Gregor; Todd Evans; Shuibing Chen; Lei Tan; Henrik Molina; Nicholas Sheets; Sergey A Shiryaev; Alexey V Terskikh; Amy S Gladfelter; Sujan Shresta; Zhiheng Xu; Joseph G Gleeson

doi:10.1016/j.neuron.2019.01.010

Zika Virus Protease Cleavage of Host Protein Septin-2 Mediates Mitotic Defects in Neural Progenitors

Neuron. 2019 Mar 20;101(6):1089-1098.e4. doi: 10.1016/j.neuron.2019.01.010. Epub 2019 Jan 31.

Authors

Hongda Li¹, Laura Saucedo-Cuevas¹, Ling Yuan², Danica Ross³, Anide Johansen¹, Daniel Sands³, Valentina Stanley³, Alicia Guemez-Gamboa¹, Anne Gregor¹, Todd Evans⁴, Shuibing Chen⁴, Lei Tan⁴, Henrik Molina⁵, Nicholas Sheets⁶, Sergey A Shiryaev⁷, Alexey V Terskikh⁷, Amy S Gladfelter⁸, Sujan Shresta⁶, Zhiheng Xu², Joseph G Gleeson⁹

Affiliations

¹ Laboratory for Pediatric Brain Disease, The Rockefeller University, New York, NY 10065, USA; Howard Hughes Medical Institute, Rady Children's Institute of Genomic Medicine, Department of Neurosciences, University of California, San Diego, San Diego, CA 92093, USA.
² Institute of Genetics & Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
³ Howard Hughes Medical Institute, Rady Children's Institute of Genomic Medicine, Department of Neurosciences, University of California, San Diego, San Diego, CA 92093, USA.
⁴ Department of Surgery, Weill Cornell Medicine, New York, NY 10065, USA.
⁵ Proteomics Resource Center, The Rockefeller University, New York, NY 10065, USA.
⁶ La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
⁷ Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
⁸ Department of Biology, Howard Hughes Medical Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁹ Laboratory for Pediatric Brain Disease, The Rockefeller University, New York, NY 10065, USA; Howard Hughes Medical Institute, Rady Children's Institute of Genomic Medicine, Department of Neurosciences, University of California, San Diego, San Diego, CA 92093, USA. Electronic address: jogleeson@ucsd.edu.

Abstract

Zika virus (ZIKV) targets neural progenitor cells in the brain, attenuates cell proliferation, and leads to cell death. Here, we describe a role for the ZIKV protease NS2B-NS3 heterodimer in mediating neurotoxicity through cleavage of a host protein required for neurogenesis. Similar to ZIKV infection, NS2B-NS3 expression led to cytokinesis defects and cell death in a protease activity-dependent fashion. Among binding partners, NS2B-NS3 cleaved Septin-2, a cytoskeletal factor involved in cytokinesis. Cleavage of Septin-2 occurred at residue 306 and forced expression of a non-cleavable Septin-2 restored cytokinesis, suggesting a direct mechanism of ZIKV-induced neural toxicity. VIDEO ABSTRACT.

Keywords: Zika; activated caspase; cytokinesis; microcephaly; protease; septin.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Video-Audio Media

MeSH terms

Apoptosis*
Cytokinesis*
Cytoskeleton / metabolism
HEK293 Cells
HeLa Cells
Humans
Mitosis*
Neural Stem Cells / metabolism*
Neurogenesis
RNA Helicases / metabolism
Septins / metabolism*
Serine Endopeptidases / metabolism
Viral Nonstructural Proteins / metabolism*
Zika Virus / metabolism*

Substances

NS2B protein, flavivirus
NS3 protein, flavivirus
Viral Nonstructural Proteins
Serine Endopeptidases
SEPTIN2 protein, human
Septins
RNA Helicases

Abstract

Publication types

MeSH terms

Substances

Grants and funding