Browsing by Subject "Amino acid transport"

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    A Member of an Ancient Family of Bacterial Amino Acids Transporters Contributes to Chlamydia Nutritional Virulence and Immune Evasion
    (American Society for Microbiology, 2023) Banerjee, Arkaprabha; Sun, Yuan; Muramatsu, Matthew K.; Toh, Evelyn; Nelson, David E.; Microbiology and Immunology, School of Medicine
    Many obligate intracellular bacteria, including members of the genus Chlamydia, cannot synthesize a variety of amino acids de novo and acquire these from host cells via largely unknown mechanisms. Previously, we determined that a missense mutation in ctl0225, a conserved Chlamydia open reading frame of unknown function, mediated sensitivity to interferon gamma. Here, we show evidence that CTL0225 is a member of the SnatA family of neutral amino acid transporters that contributes to the import of several amino acids into Chlamydia cells. Further, we show that CTL0225 orthologs from two other distantly related obligate intracellular pathogens (Coxiella burnetii and Buchnera aphidicola) are sufficient to import valine into Escherichia coli. We also show that chlamydia infection and interferon exposure have opposing effects on amino acid metabolism, potentially explaining the relationship between CTL0225 and interferon sensitivity. Overall, we show that phylogenetically diverse intracellular pathogens use an ancient family of amino acid transporters to acquire host amino acids and provide another example of how nutritional virulence and immune evasion can be linked in obligate intracellular pathogens.
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    GCN2 eIF2 kinase promotes prostate cancer by maintaining amino acid homeostasis
    (eLife Sciences, 2022-09-15) Cordova, Ricardo A.; Misra, Jagannath; Amin, Parth H.; Klunk, Anglea J.; Damayanti, Nur P.; Carlson, Kenneth R.; Elmendorf, Andrew J.; Kim, Hyeong-Geug; Mirek, Emily T.; Elzey, Bennet D.; Miller, Marcus J.; Dong, X. Charlie; Cheng, Liang; Anthony, Tracy G.; Pili, Roberto; Wek, Ronald C.; Staschke, Kirk A.; Biochemistry and Molecular Biology, School of Medicine
    A stress adaptation pathway termed the integrated stress response has been suggested to be active in many cancers including prostate cancer (PCa). Here, we demonstrate that the eIF2 kinase GCN2 is required for sustained growth in androgen-sensitive and castration-resistant models of PCa both in vitro and in vivo, and is active in PCa patient samples. Using RNA-seq transcriptome analysis and a CRISPR-based phenotypic screen, GCN2 was shown to regulate expression of over 60 solute-carrier (SLC) genes, including those involved in amino acid transport and loss of GCN2 function reduces amino acid import and levels. Addition of essential amino acids or expression of 4F2 (SLC3A2) partially restored growth following loss of GCN2, suggesting that GCN2 targeting of SLC transporters is required for amino acid homeostasis needed to sustain tumor growth. A small molecule inhibitor of GCN2 showed robust in vivo efficacy in androgen-sensitive and castration-resistant mouse models of PCa, supporting its therapeutic potential for the treatment of PCa.