Poster abstracts
Poster number 69 submitted by Amra Ismail
ADAR1 Suppresses PKR-Mediated Stress Granule Oscillations in Interferon-Stimulated Cells
Amra Ismail (Department of Biochemistry and Center for RNA Science and Therapeutics, Case Western Reserve University, Cleveland, OH), Saad Badat (Department of Biochemistry and Center for RNA Science and Therapeutics, Case Western Reserve University, Cleveland, OH), Joseph M. Luna (Department of Biochemistry and Center for RNA Science and Therapeutics, Case Western Reserve University, Cleveland, OH)
Abstract:
Stress granules (SGs) are cytoplasmic condensates traditionally viewed as stable indicators of cellular stress. Our study identifies previously unobserved dynamic behaviors of SGs and suggests an important role for ADAR1 in regulating stress responses. We demonstrate that in ADAR1-depleted cells, interferon stimulation induces periodic formation and dissolution of SGs. This oscillatory behavior is mediated by protein kinase R (PKR) activation in response to double-stranded RNA (dsRNA) accumulation. In wild-type cells, ADAR1 suppresses this oscillation by editing dsRNA, preventing PKR activation. Using high-resolution live-cell imaging and machine-learning classification, we quantified SG dynamics for up to 3 days. In ADAR1-knockout cells, we observed initial synchronized SG oscillations followed by unsynchronized patterns. These oscillations persisted after interferon removal and required an intact interferon signaling pathway. Mechanistically, interferon treatment of ADAR1-depleted cells establishes an auto-activation loop coupled with negative feedback from PKR activation, enabling self-perpetuating SG oscillation. Conversely, PKR knockout resulted in loss of SGs and reduced interferon levels, further confirming PKR's central role in this process. Our findings reveal a previously unknown function of ADAR1 in suppressing stress granule oscillations and provide insights into the interplay between RNA editing, innate immunity, and cellular stress pathways. This work offers a new perspective on stress granule dynamics and their potential role in antiviral responses, laying the groundwork for understanding how cells fine-tune their response to persistent stressors.
Keywords: Stress Granules, RNA-binding proteins