Date of Degree

9-2018

Document Type

Dissertation

Degree Name

Ph.D.

Program

Biochemistry

Advisor

Zahra Zakeri

Committee Members

Wilma Saffran

Ana Sesma Fernandez

Cathy Savage Dunn

Michael Overholtzer

Subject Categories

Cell Biology | Infectious Disease | Molecular Biology | Virology | Virus Diseases

Keywords

Dengue, autophagy, ER stress, Unfolded Protein Response, PERK, Zika, Ataxia Telangiectasia Mutated kinase

Abstract

Dengue, the most rapidly spreading flavivirus, threatens to affect almost half of the human global population. We previously showed that dengue-2 protects canine kidney cells (MDCK) from cytotoxic chemicals. We showed, independently, that cell protection, as well as viral replication and maturation, are positively regulated by PI3K-dependent autophagy. However, we had not identified the specific pathway that induces autophagy in infected cells. The current study explores the role of a specific branch of the endoplasmic reticulum (ER) stress-mediated Unfolded Protein Response (UPR), the PERK/eIF2α/ATF4 pathway in the induction of autophagy by Dengue. We studied the relationship between the PERK pathway and induction of autophagy in infected MDCK and MEF cells. We extended this study to determine whether PERK activity correlates with protection of infected cells. Finally, we identified Ataxia Telangiectasia Mutated (ATM), a DNA damage response (DDR) protein as an upstream regulator of PERK, autophagy, and cell protection. Our data show that, when dengue infects cells, ATM is an early regulator that activates PERK, autophagy and cell protection. Since PERK and autophagy have been implicated in viral production, the current study identifies several putative targets for antiviral therapy, although these targets also serve multiple housekeeping functions (stress response, protein folding, and homeostasis) in the cell. Future studies should focus on the links between these pathways and identify an antiviral target that is redundant or non-essential for the host cell.

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