Date of Award

Spring 2026

Language

English

Embargo Period

4-30-2026

Document Type

Master's Thesis

Degree Name

Master of Science (MS)

College/School/Department

Department of Biological Sciences

Program

Biology

First Advisor

Cara T. Pager

Second Advisor

Morgan A. Sammons

Committee Members

Kaalak Reddy, Gabriele Fuchs

Keywords

ATF4, ATF3, ISR, bioinformatics

Subject Categories

Bioinformatics

Abstract

The integrated stress response (ISR) is a critical cellular pathway that coordinates adaptation to various stressors, including endoplasmic reticulum (ER) stress, amino acid (AA) starvation, heme deficiency, and viral infection. Central to this pathway are the transcription factors ATF4 and its downstream target ATF3, which regulate gene expression programs that influence cell survival, metabolism, and immune responses. While previous studies have identified ATF3 as an antiviral factor during Zika virus (ZIKV) infection, the broader relationship between ATF3 and ATF4 across multiple branches of the ISR remains incompletely understood.

In this study, I employed multi-omic approaches to characterize the roles of ATF3 and ATF4 in response to ER stress, AA starvation, and ZIKV infection using A549 cell lines possessing or lacking either ATF3 or ATF4. Proteomic analysis demonstrates that ATF3 functions as a restriction factor during ZIKV infection, promoting antiviral pathways and regulating immune signaling. Further analysis revealed disruption of RNA-protein dynamics, indicating widespread dysregulation of host cellular processes.

Transcriptomics was used to compare ATF3 and ATF4 wild-type and knockout cell lines under multiple ISR-inducing conditions. Results indicate that while loss of either transcription factor does not globally disrupt differential gene expression patterns, it alters the identity and magnitude of stress-responsive genes. ATF3 and ATF4 regulate distinct but overlapping biological processes in a context-dependent manner. ATF3 is primarily associated with antiviral responses and RNA processing during ER stress, whereas ATF4 is more strongly linked to amino acid metabolism, ER stress adaptation, and regulation of cell growth and proliferation. Notably, antiviral pathways were largely independent of ATF4 but dependent on ATF3, supporting their opposing roles during ZIKV infection.

Collectively, these findings highlight the complementary and context-specific functions of ATF3 and ATF4 in coordinating cellular stress responses. This work provides a foundation for future studies aimed at understanding how modulation of these transcription factors may influence host-virus interactions and stress adaptation pathways.

License

This work is licensed under the University at Albany Standard Author Agreement.

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