Regulation of Protein Synthesis in Stress and Disease
Cells must constantly adapt to environmental and physiological stresses in order to survive. In actively growing cells, energetic resources are devoted to biosynthesis and proliferation, while in differentiated cells, resources support specialized cellular functions. However, when faced with acute stresses, such as viral infection, oxidative stress, heat shock, or exposure to heavy metals, cells rapidly reprogram gene expression to conserve energy and prioritize survival.
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Careful calibration of these responses is essential. An insufficient response may lead to cell death, with especially devastating consequences in long-lived, terminally differentiated cells such as neurons. Conversely, cancer cells often hijack stress-adaptive pathways to promote their own survival at the expense of surrounding tissue. Viruses likewise remodel host stress responses to ensure their mRNAs are translated even when global protein synthesis is suppressed.
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Our lab investigates the molecular mechanisms by which stress reshapes RNA metabolism and translation. We use a combination of microscopy, biochemistry, and high-throughput methods such as Ribo-Seq, RNA-Seq, and proteomics to define how ribosome biogenesis, translation initiation, and 5′ UTR architecture govern selective mRNA translation. By studying contexts including viral infection, environmental toxins, tumor-associated stress, and aging, our goal is to reveal fundamental principles of stress-responsive gene expression and identify new opportunities for therapeutic intervention.
Regulation of Translation Initiation
mRNA translation is the process by which ribosomes decode mRNAs to synthesize proteins, and it is one of the fastest points of control during stress. When cells encounter acute stress, the translation of pro-growth and housekeeping mRNAs is broadly downregulated, while production of pro-survival factors and detoxifying enzymes is selectively maintained. This selectivity is governed primarily at the level of translation initiation, where the cell can regulate assembly of initiation complexes or modulate recognition of start codons.
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These regulatory events often culminate in the formation of stress granules: non-membranous condensates that sequester stalled pre-initiation complexes. Yet, despite these global controls, subsets of mRNAs escape inhibition and continue to be translated. Our lab investigates how stress-induced translation inhibition is established, what downstream consequences it has for cellular physiology, and the molecular mechanisms that allow specific mRNAs to bypass regulation. By defining these principles, we aim to understand how cells balance energy conservation with selective protein synthesis, and how defects in this balance contribute to disease and aging.
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Ribosome Biogenesis
The production of ribosomes is one of the most energy-intensive tasks a cell undertakes. Each human ribosome contains 80 ribosomal proteins and four long non-coding RNAs, and its assembly requires the coordinated action of hundreds of assembly factors, processing enzymes, and RNA modification enzymes. This elaborate process produces one of the most complex molecular machines in the cell, and proliferating cells must duplicate their entire ribosome pool (up to 10 million ribosomes) with every cell division.
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Our lab investigates the molecular mechanisms that ensure the rapid and precise assembly of ribosomes, and how this process is remodeled under stress, when the demand for new ribosomes declines. We are particularly focused on how rRNA processing and modification are altered in response to acute stresses such as oxidative damage, heavy metal exposure, and viral infection. These adaptive changes in ribosome biogenesis are increasingly linked to human disease, including cancer, neurodegeneration, and age-associated decline in proteostasis. By defining how ribosome production is tuned to cellular conditions, we aim to uncover new principles of stress-responsive gene expression and their relevance to disease.
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Viral mRNA Translation
Viruses depend entirely on the host’s protein synthesis machinery to express their genes, yet infection typically triggers modulation of host cap-dependent translation. To overcome this, viruses have evolved strategies that allow their mRNAs to be translated even when global protein synthesis is suppressed.
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Our lab focuses on how viruses, including influenza A virus and respiratory syncytial virus, exploit non-canonical translation mechanisms to ensure robust viral protein production. These viral mRNAs often contain unusually short 5′ UTRs that are not sufficient for canonical translation initiation. We are particularly interested in the role of alternative cap-binding proteins in supporting viral translation under conditions where host translation is restricted. In contrast, other viruses, such as Ebola virus, rely on long and structured 5′ UTRs that impose a stronger dependence on canonical initiation pathways. By comparing viruses with short versus long 5′ UTRs, we aim to define the rules by which viral mRNAs compete with cellular mRNAs for ribosomes and initiation factors. These studies not only uncover fundamental mechanisms of gene regulation during infection but also reveal potential targets for broad-spectrum antiviral therapies.
