FK506-binding protein, FKBP12, promotes serine utilization and negatively regulates threonine deaminase in fission yeast
Mayuki Sasaki,
Shinichi Nishimura,
Yoko Yashiroda,
Akihisa Matsuyama,
Hideaki Kakeya,
Minoru Yoshida
Affiliations
Mayuki Sasaki
Department of Biotechnology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan
Shinichi Nishimura
Department of Biotechnology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan; Collaborative Research Institute for Innovative Microbiology, The University of Tokyo, Tokyo 113-8657, Japan; Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan; Corresponding author
Yoko Yashiroda
RIKEN Center for Sustainable Resource Science, Saitama 351-0198, Japan
Akihisa Matsuyama
RIKEN Center for Sustainable Resource Science, Saitama 351-0198, Japan
Hideaki Kakeya
Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan
Minoru Yoshida
Department of Biotechnology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan; Collaborative Research Institute for Innovative Microbiology, The University of Tokyo, Tokyo 113-8657, Japan; RIKEN Center for Sustainable Resource Science, Saitama 351-0198, Japan; Corresponding author
Summary: FK506-binding protein with a molecular weight of 12 kDa (FKBP12) is a receptor of the immunosuppressive drugs, FK506 and rapamycin. The physiological functions of FKBP12 remain ambiguous because of its nonessentiality and multifunctionality. Here, we show that FKBP12 promotes the utilization of serine as a nitrogen source and regulates the isoleucine biosynthetic pathway in fission yeast. In screening for small molecules that inhibit serine assimilation, we found that the growth of fission yeast cells in medium supplemented with serine as the sole nitrogen source, but not in glutamate-supplemented medium, was suppressed by FKBP12 inhibitors. Knockout of FKBP12 phenocopied the action of these compounds in serine-supplemented medium. Metabolome analyses and genetic screens identified the threonine deaminase, Tda1, to be regulated downstream of FKBP12. Genetic and biochemical analyses unveiled the negative regulation of Tda1 by FKBP12. Our findings reveal new roles of FKBP12 in amino acid biosynthesis and nitrogen metabolism homeostasis.
