Physiological function of FKBP12, a primary target of rapamycin/FK506: a newly identified role in transcription of ribosomal protein genes in yeast.

Koji Kasahara

Current genetics 2021 Jun

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In this review, we have summarized the information from a study on FKBP12 (FK506 binding protein 12 kDa) with a view to understand its drug-free, physiological roles in transcription of ribosomal protein gene in Saccharomyces cerevisiae. FKBP12 with peptidyl-prolylisomerase (PPIase) activity is widely conserved among many eukaryotes. FKBP12 is a primary target for the two structurally related drugs, FK506 and rapamycin. FKBP12 bound with FK506 or rapamycin inhibits calcineurin and target of rapamycin complex 1 (TORC1), respectively. The molecular mechanisms of the effect of FKBP12 in the presence of these drugs have been elucidated. Conversely, the physiological role of FKBP12 has been unclear, especially in yeast. Our study revealed that the deletion of FPR1 (FK506-sensitive prolinerotamase 1 gene), which encodes yeast FKBP12, induced severe growth defect synthetically with deletion of HMO1 (high mobility group family 1). HMO1 encodes an HMGB family protein involved in transcription of ribosomal component genes. Fpr1 was shown to bind specifically to the promoters of ribosomal protein genes (RPGs) dependent on Rap1 (repressor/activator binding protein 1). Importantly, Fpr1 and Hmo1 promote the binding of Fhl1/Ifh1 (forkhead-like 1/interacts with forkhead 1), key regulators of RPG transcription, to certain RPG promoters independently and/or cooperatively with each other. Taken together, we conclude that Fpr1 physiologically functions as transcription factor of RPGs in S. cerevisiae. To our knowledge, this is the first study to demonstrate that FKBP12 participates in ribosome synthesis independently of drugs, and it may also provide a clue to the unidentified function of other PPIase proteins.

Citation

Koji Kasahara. Physiological function of FKBP12, a primary target of rapamycin/FK506: a newly identified role in transcription of ribosomal protein genes in yeast. Current genetics. 2021 Jun;67(3):383-388