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Hyung Don Ryoo

Hyung Don Ryoo, PhD

Professor, Department of Cell Biology

Keywords
stress response signaling, developmental genetics, gene expression regulation, neurodegeneration
Summary

Our laboratory is interested in understanding how metazoan cells adapt to various stress conditions that could otherwise impair animal development and underlie 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 play protective roles in this model by inducing chaperones and rhodopsin degrading enzymes (Kang and Ryoo, 2009; Huang et al., 2018). We have also established that UPR is essential for normal Drosophila development to help resolve physiological stress in specific cell types (Ryoo et al., 2007; Huang et al., 2017). 

More recently, we began investigating a related, but a 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 animal physiology and disease. We began with the discovery that this pathway has a second node of translational inhibition imposed by an ATF4 downstream gene 4E-BP (Kang et al., 2017). We further showed that 4E-BP has a selective effect that allows overall enhanced stress response, including those against amino acid deprivation and bacterial infection (Kang et al., 2017; Vasudevan et al., 2018). Identification of the ATF4-4E-BP link allowed us to generate an in vivo ATF4 signaling reporter, which we used to perform genetic screens to identify ATF4 signaling mediators. The first significant outcome of this approach was the identification of noncanonical translation initiation factors, eIF2D and DENR, that are specifically required for ATF4’s translational induction (Vasudevan et al., 2020). The findings provide mechanistic insights by which stressed cells paradoxically induce ATF4 when eIF2a kinases suppress overall mRNA translation. As ISR affects a growing list of degenerative and metabolic diseases, these discoveries may have direct therapeutic impact. 

Phone

212-263-7257

Academic office

540 First Avenue

SKI 5th Floor, 5-2

New York, NY 10016

Lab Website
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Advsr Cellular Molecular Bio Trng Program

Co Dir CMB Training Program

Inst Lecturer-Cell Bio & Histology

PhD from Columbia University

The Rockefeller University, Strang Laboratory of Apoptosis and Cancer Biology

Mitra, Sahana; Ryoo, Hyung Don

Developmental biology (Orlando). 2021 Oct; 478:205-211

Oh, Yangkyun; Lai, Jason Sih-Yu; Min, Soohong; Huang, Huai-Wei; Liberles, Stephen D; Ryoo, Hyung Don; Suh, Greg S B

Neuron. 2021 Jun 16; 109(12):1979-1995.e6

Vasudevan, Deepika; Neuman, Sarah D; Yang, Amy; Lough, Lea; Brown, Brian; Bashirullah, Arash; Cardozo, Timothy; Ryoo, Hyung Don

Nature communications. 2020 09 16; 11(1):4677

Krishnaswamy, S; Huang, H-W; Marchal, I S; Ryoo, H D; Sigurdsson, E M

Neurobiology of disease. 2020 Jan 23; 104770

Mitra, Sahana; Ryoo, Hyung Don

Journal of cell science. 2019 02 15; 132(5):

Huang, Huai-Wei; Brown, Brian; Chung, Jaehoon; Domingos, Pedro M; Ryoo, Hyung Don

Cell reports. 2018 Feb 06; 22(6):1384-1391

Vasudevan, Deepika; Clark, Nicholas K; Sam, Jessica; Cotham, Victoria C; Ueberheide, Beatrix; Marr, Michael T 2nd; Ryoo, Hyung Don

Cell reports. 2017 Nov 21; 21(8):2039-2047