The etiology of multiple human diseases – including retinopathies, atherosclerosis, diabetes, and neurodegenerative disorders – are closely linked to the activation of cellular stress response pathways. In addition to their impact on pathologies, these pathways are also crucial during development, with mutations in pathway components resulting in congenital diseases. The Integrated Stress Response (ISR) pathway, as the name suggests, utilizes a family of kinases to counter various cellular stresses, including protein misfolding, amino acid deprivation, pathogenic infection, and oxidative stress. The ISR ameliorates stress by transiently limiting mRNA translation while simultaneously engaging a stress-response transcriptional program. How these stress response transcripts are translated when ISR is limiting mRNA translation is the central theme of the lab’s research:
- What are the mRNA sequences that set stress response transcripts apart?
- What are the specialized factors that allow for selective translation of these transcripts?
- Do these factors only act during stress; what are they doing during homeostasis/development?
We use a multi-faceted approach to answer these questions: our primary discovery platform is the fruit fly Drosophila, which provides necessary physiological context to our research. To study the effects of translation regulation on disease progression, we utilize a Drosophila model of Retinitis Pigmentosa, a progressive retinal degeneration disorder characterized by ISR activation. We also use translation profiling methods to study the molecular biology of our favorite translation events. Finally, we have multiple collaborative initiatives to take our research into vertebrate models, which allows us to assess the therapeutic impact of our work.
- Shyam R, Shu DY, Zuniga-Sanchez E, Vasudevan D. Editorial: Molecular mechanisms in ocular development and disease.. Front Cell Dev Biol. 2023;11():1244123. doi: 10.3389/fcell.2023.1244123. PubMed PMID: 37457294;
- Vasudevan D, Neuman SD, Yang A, Lough L, Brown B, Bashirullah A, Cardozo T, Ryoo HD. Translational induction of ATF4 during integrated stress response requires noncanonical initiation factors eIF2D and DENR.. Nat Commun. 2020 Sep 16;11(1):4677. doi: 10.1038/s41467-020-18453-1. PubMed PMID: 32938929;
- Zhang A, Berardinelli SJ, Leonhard-Melief C, Vasudevan D, Liu TW, Taibi A, Giannone S, Apte SS, Holdener BC, Haltiwanger RS. O-Fucosylation of ADAMTSL2 is required for secretion and is impacted by geleophysic dysplasia-causing mutations.. J Biol Chem. 2020 Nov 13;295(46):15742-15753. doi: 10.1074/jbc.RA120.014557. PubMed PMID: 32913123;
- Lough L, Sherman D, Beccera-Flores M, Lavinda O, Ni E, Wang H, Tibes R, Cardozo T. Triazolo[4,5-d]pyrimidines as Validated General Control Nonderepressible 2 (GCN2) Protein Kinase Inhibitors Reduce Growth of Leukemia Cells.. Comput Struct Biotechnol J. 2018;16():350-360. doi: 10.1016/j.csbj.2018.09.003. PubMed PMID: 30364637;
- Vasudevan D, Clark NK, Sam J, Cotham VC, Ueberheide B, Marr MT 2nd, Ryoo HD. The GCN2-ATF4 Signaling Pathway Induces 4E-BP to Bias Translation and Boost Antimicrobial Peptide Synthesis in Response to Bacterial Infection.. Cell Rep. 2017 Nov 21;21(8):2039-2047. doi: 10.1016/j.celrep.2017.10.096. PubMed PMID: 29166596;
- Ryoo HD, Vasudevan D. Two distinct nodes of translational inhibition in the Integrated Stress Response.. BMB Rep. 2017 Nov;50(11):539-545. . PubMed PMID: 28803610;
- Kang MJ, Vasudevan D, Kang K, Kim K, Park JE, Zhang N, Zeng X, Neubert TA, Marr MT 2nd, Ryoo HD. 4E-BP is a target of the GCN2-ATF4 pathway during Drosophila development and aging.. J Cell Biol. 2017 Jan 2;216(1):115-129. doi: 10.1083/jcb.201511073. PubMed PMID: 27979906;
- Dubail J, Vasudevan D, Wang LW, Earp SE, Jenkins MW, Haltiwanger RS, Apte SS. Impaired ADAMTS9 secretion: A potential mechanism for eye defects in Peters Plus Syndrome.. Sci Rep. 2016 Sep 30;6():33974. doi: 10.1038/srep33974. PubMed PMID: 27687499;
- Vasudevan D, Ryoo HD. Detection of Cell Death in Drosophila Tissues.. Methods Mol Biol. 2016;1419():131-44. doi: 10.1007/978-1-4939-3581-9_11. PubMed PMID: 27108437;
- Valero-González J, Leonhard-Melief C, Lira-Navarrete E, Jiménez-Osés G, Hernández-Ruiz C, Pallarés MC, Yruela I, Vasudevan D, Lostao A, Corzana F, Takeuchi H, Haltiwanger RS, Hurtado-Guerrero R. A proactive role of water molecules in acceptor recognition by protein O-fucosyltransferase 2.. Nat Chem Biol. 2016 Apr;12(4):240-6. doi: 10.1038/nchembio.2019. PubMed PMID: 26854667;
- Vasudevan D, Ryoo HD. Regulation of Cell Death by IAPs and Their Antagonists.. Curr Top Dev Biol. 2015;114():185-208. doi: 10.1016/bs.ctdb.2015.07.026. PubMed PMID: 26431568;
- Vasudevan D, Takeuchi H, Johar SS, Majerus E, Haltiwanger RS. Peters plus syndrome mutations disrupt a noncanonical ER quality-control mechanism.. Curr Biol. 2015 Feb 2;25(3):286-295. doi: 10.1016/j.cub.2014.11.049. PubMed PMID: 25544610;
- Vasudevan D, Haltiwanger RS. Novel roles for O-linked glycans in protein folding.. Glycoconj J. 2014 Oct;31(6-7):417-26. doi: 10.1007/s10719-014-9556-4. PubMed PMID: 25186198;
University of Pittsburgh
Department of Cell Biology