Browsing by Author "Rosario, Spencer R."

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    A Translational Regulatory Mechanism Mediated by Hypusinated Eukaryotic Initiation Factor 5A Facilitates β-Cell Identity and Function
    (American Diabetes Association, 2024) Connors, Craig T.; Villaca, Catharina B. P.; Anderson-Baucum, Emily K.; Rosario, Spencer R.; Rutan, Caleb D.; Childress, Paul J.; Padgett, Leah R.; Robertson, Morgan A.; Mastracci, Teresa L.; Biology, School of Science
    As professional secretory cells, β-cells require adaptable mRNA translation to facilitate a rapid synthesis of proteins, including insulin, in response to changing metabolic cues. Specialized mRNA translation programs are essential drivers of cellular development and differentiation. However, in the pancreatic β-cell, the majority of factors identified to promote growth and development function primarily at the level of transcription. Therefore, despite its importance, the regulatory role of mRNA translation in the formation and maintenance of functional β-cells is not well defined. In this study, we have identified a translational regulatory mechanism mediated by the specialized mRNA translation factor eukaryotic initiation factor 5A (eIF5A), which facilitates the maintenance of β-cell identity and function. The mRNA translation function of eIF5A is only active when it is posttranslationally modified ("hypusinated") by the enzyme deoxyhypusine synthase (DHPS). We have discovered that the absence of β-cell DHPS in mice reduces the synthesis of proteins critical to β-cell identity and function at the stage of β-cell maturation, leading to a rapid and reproducible onset of diabetes. Therefore, our work has revealed a gatekeeper of specialized mRNA translation that permits the β-cell, a metabolically responsive secretory cell, to maintain the integrity of protein synthesis necessary during times of induced or increased demand.
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    Downregulation of IRF8 in alveolar macrophages by G-CSF promotes metastatic tumor progression
    (Elsevier, 2024-02-10) Tzetzo, Stephanie L.; Kramer, Elliot D.; Mohammadpour, Hemn; Kim, Minhyung; Rosario, Spencer R.; Yu, Han; Dolan, Melissa R.; Oturkar, Chetan C.; Morreale, Brian G.; Bogner, Paul N.; Stablewski, Aimee B.; Benavides, Fernando J.; Brackett, Craig M.; Ebos, John M. L.; Das, Gokul M.; Opyrchal, Mateusz; Nemeth, Michael J.; Evans, Sharon S.; Abrams, Scott I.; Medicine, School of Medicine
    Tissue-resident macrophages (TRMs) are abundant immune cells within pre-metastatic sites, yet their functional contributions to metastasis remain incompletely understood. Here, we show that alveolar macrophages (AMs), the main TRMs of the lung, are susceptible to downregulation of the immune stimulatory transcription factor IRF8, impairing anti-metastatic activity in models of metastatic breast cancer. G-CSF is a key tumor-associated factor (TAF) that acts upon AMs to reduce IRF8 levels and facilitate metastasis. Translational relevance of IRF8 downregulation was observed among macrophage precursors in breast cancer and a CD68hiIRF8loG-CSFhi gene signature suggests poorer prognosis in triple-negative breast cancer (TNBC), a G-CSF-expressing subtype. Our data highlight the underappreciated, pro-metastatic roles of AMs in response to G-CSF and identify the contribution of IRF8-deficient AMs to metastatic burden. AMs are an attractive target of local neoadjuvant G-CSF blockade to recover anti-metastatic activity.