Hyung Don Ryoo, PhD

Our laboratory is interested in understanding how metazoan cells adapt to various stress conditions that could otherwise contribute to human diseases. Our strategy is to use the genetic and cell biological tools of Drosophila as a model system.

We are currently investigating two different types of stress response signaling pathways. First is the Unfolded Protein Response (UPR), which refers to gene expression regulatory pathways activated by misfolded protein overload in the endoplasmic reticulum (ER). Our group was the first to employ Drosophila genetics to investigate UPR signaling mechanisms (Ryoo et al., 2007). This approach has allowed us to establish the physiological and pathological relevance of these stress response mechanisms in various in vivo contexts. One particular disease model that we have extensively studied is a Drosophila model for Retinitis Pigmentosa, in which mutant rhodopsins cause age-related loss of photoreceptors. Specifically, we demonstrated that rhodopsin misfolding in the ER is the contributing cause of the retinal degeneration in this model (Ryoo et al., 2007; Kang and Ryoo, 2009; Kang et al., 2012). We further showed that UPR pathways are essential to resolve physiological and pathological stresses in specific cell types (Kang and Ryoo, 2009; Huang et al., 2017; Huang et al., 2018). 

More recently, we began investigating a related, but distinct, stress-response pathway referred to as the Integrated Stress Response (ISR). This pathway is initiated by stress-activated eIF2a kinases, which cause translational attenuation and a paradoxical increase in the translation of the transcription factor ATF4. This pathway is activated by diverse stress conditions that include amino acid deprivation and ER stress. One of our major goals is to understand how this regulatory mechanism works and how it affects physiology and disease. We are particularly interested in understanding the translational regulatory mechanisms required for ATF4 induction, among which are noncanonical translation initiation factors, eIF2D and DENR (Vasudevan et al., 2020). In addition, we are investigating how the transcription factor Xrp1 is induced by this pathway (Brown et al., 2021). Finally, we are actively testing how these regulators affect Drosophila models of Retinitis Pigmentosa and Parkinson's disease. As ISR affects a growing list of degenerative and metabolic diseases, these discoveries may have direct therapeutic impact.