| Summary: | Summary: Sufficient amino acid supplies are critical for protein synthesis and, thus, cell growth and proliferation. Specialized transporters mediate amino acid exchange across membranes and their regulation is critical for amino acid homeostasis. Here, we report that the DNA- and RNA-binding protein YBX3 regulates the expression of amino acid transporters. To investigate the functions of YBX3, we integrated proteomic and transcriptomic data from cells depleted of YBX3 with analyses of YBX3 RNA binding sites to identify RNAs directly regulated by YBX3. The data implicate YBX3 as a RNA-binding protein that regulates distinct sets of mRNAs by discrete mechanisms, including mRNA abundance. Among direct YBX3 targets, two solute carrier (SLC) amino acid transporters (SLC7A5 and SLC3A2) were identified. We show that YBX3 stabilizes these SLC mRNAs and that YBX3 depletion diminishes the expression of SLC7A5/SLC3A2, which specifically reduces SLC7A5/SLC3A2 amino acid substrates. Thus, YBX3 emerges as a key regulator of amino acid levels. : Cooke et al. uncover an unanticipated function of YBX3 in controlling amino acid levels using a multi-omics approach. The authors demonstrate that YBX3 directly regulates SLC7A5 mRNA stability. Depletion of YBX3 selectively reduces intracellular levels of SLC7A5-imported amino acids, thus establishing YBX3 as a key regulator of amino acid homeostasis. Keywords: YBX3, SLC7A5, SLC3A2, mRNA stability, amino acid transport, RNA binding protein, multi-omic
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