RAPID: Impact of SARS-CoV2 on function of the cellular tRNA methyltransferase 1 and redox homeostasis

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Due to the global pandemic caused by SARS-CoV2, there is an urgent need to understand how coronavirus infection affects host cellular processes. This project will explore a recently discovered link between a SARS-CoV2 protein-cleaving enzyme and a human protein that may be its target. Combined biochemical, molecular, and cellular approaches will be used to study how interaction of the viral and human proteins can alter normal cellular functions. The outcomes are expected to uncover targets for therapeutic intervention to address the COVID-19 pandemic. The project will provide training opportunities for two graduate students who will carry out the research. Recently, a novel connection was discovered between the main protease of SARS-CoV2, called Nsp5, and the human tRNA methyltransferase enzyme known as TRMT1. TRMT1 methylates a specific position (m2.2G) in more than half of all cellular tRNAs and in many mitochondrial tRNAs, and TRMT1 is known to be essential for normal levels of protein synthesis and for redox homeostasis in human cells. TRMT1 contains an amino acid sequence that may be a target for cleavage by Nsp5, but the biological effects and downstream consequences of the Nsp5-TRMT1 interaction are unknown. This project will focus on three aims: determining the effects of Nsp5 binding on TMRT1's stability and ability to bind tRNAs; identifying TRMT1-dependent pathways that are modulated through Nsp5 interaction with TRMT1; and testing how TRMT1-dependent pathways impact the SARS-CoV2 life cycle. By understanding how SARS-CoV2 infection affects TRMT1 function, the project will yield insight into novel strategies that viruses employ to alter host gene expression and metabolism. The results could aid in development of new drug therapies or biomarkers for detecting coronavirus infection. This RAPID award is made by the Genetic Mechanisms Program in the Division of Molecular and Cellular Biosciences, using funds from the Coronavirus Aid, Relief, and Economic Security (CARES) Act.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.