y research interest is in understanding how animal development, tissue homeostasis and age-related disease outcomes are affected by the Unfolded Protein Response (UPR) and the related Integrated Stress Response (ISR), which are signaling pathways activated by excessive stress in the endoplasmic reticulum (ER). For my research, I primarily use Drosophila as a model organism. I was introduced to this organism during my graduate studies, when I studied the role of Hox proteins in Drosophila development under the guidance of Dr. Richard Mann (Columbia University). As a postdoc, I chose to study the mechanism of apoptosis in the laboratory of Hermann Steller’s (Rockefeller University), with the goal of applying Drosophila genetics for disease-relevant research topics. During that period, my work helped to establish the idea that ubiquitin-mediated protein degradation is heavily involved in apoptosis regulation, and that dying cells may actively send mitogenic signals for compensatory proliferation. As an independent P.I. at the New York University School of Medicine (beginning in 2005), I began focusing on UPR and ISR signaling. While these stress response pathways were mostly studied in cultured mammalian cells, my laboratory introduced the use of Drosophila genetics to this field, which has facilitated new discoveries regarding the role of these pathways in development, age-related degeneration and lifespan. We began with the study of the IRE/XBP1 branch of the UPR, starting with the development of in vivo reporters for UPR detection and the demonstration of its relevance in the progression of retinal degeneration in a Drosophila Retinitis Pigmentosa model (Ryoo, 2007; Kang, 2012; Sone 2013). Most recently, my laboratory has shifted our focus to ATF4, a transcription factor that mediates a different branch of the UPR as well as ISR signaling. We have now developed robust assay tools to study this ATF4 pathway in Drosophila, which has helped us identify new regulators of this pathway, and uncover ISR’s effects on lifespan, response to dietary restriction, innate immunity and general development (Kang 2017).
Ryoo, H., Domingos, P.M., Kang, M.J., Steller, H. Unfolded Protein Response in a Drosophila model for Retinal Degeneration. EMBO Journal 26(1): 242-252. PMC1782370 (2007).
Kang, M.J., Chung, J., Ryoo, H.D. CDK5 and MEKK1 mediate pro-apoptotic signaling following endoplasmic reticulum stress in an autosomal dominant retinitis pigmentosa model. Cell Biol. 14(4): 409-415. PMC3319494 (2012).
Sone, M., Zeng, X., Larese, J., Ryoo, H.D. A modified UPR sensing system reveals a novel tissue distribution of IRE1/XBP1 activity during normal Drosophila Cell Stress Chaperones 18(3): 307-319. PMC3631089 (2013).
Kang, M.J., Vasudevan, D., Kang, K., Kim, K., Park, J.E., Zhang, N., Zeng, X., Neubert, T.A., Marr, M.T. 2nd, Ryoo, H.D. 4E-BP is a target of the GCN2-ATF4 pathway during Drosophila development and aging. Cell Biol. 216(1): 115-129. PMC5223598 (2017).