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Fpr1, a primary target of rapamycin, functions as a transcription factor for ribosomal protein genes cooperatively with Hmo1 in Saccharomyces cerevisiae.
PLoS Genet. 2020 06; 16(6):e1008865.PG

Abstract

Fpr1 (FK506-sensitive proline rotamase 1), a protein of the FKBP12 (FK506-binding protein 12 kDa) family in Saccharomyces cerevisiae, is a primary target for the immunosuppressive agents FK506 and rapamycin. Fpr1 inhibits calcineurin and TORC1 (target of rapamycin complex 1) when bound to FK506 and rapamycin, respectively. Although Fpr1 is recognised to play a crucial role in the efficacy of these drugs, its physiological functions remain unclear. In a hmo1Δ (high mobility group family 1-deleted) yeast strain, deletion of FPR1 induced severe growth defects, which could be alleviated by increasing the copy number of RPL25 (ribosome protein of the large subunit 25), suggesting that RPL25 expression was affected in hmo1Δfpr1Δ cells. In the current study, extensive chromatin immunoprecipitation (ChIP) and ChIP-sequencing analyses revealed that Fpr1 associates specifically with the upstream activating sequences of nearly all RPG (ribosomal protein gene) promoters, presumably in a manner dependent on Rap1 (repressor/activator site binding protein 1). Intriguingly, Fpr1 promotes the binding of Fhl1/Ifh1 (forkhead-like 1/interacts with forkhead 1), two key regulators of RPG transcription, to certain RPG promoters independently of and/or cooperatively with Hmo1. Furthermore, mutation analyses of Fpr1 indicated that for transcriptional function on RPG promoters, Fpr1 requires its N-terminal domain and the binding surface for rapamycin, but not peptidyl-prolyl isomerase activity. Notably, Fpr1 orthologues from other species also inhibit TORC1 when bound to rapamycin, but do not regulate transcription in yeast, which suggests that these two functions of Fpr1 are independent of each other.

Authors+Show Affiliations

Department of Molecular Microbiology, Tokyo University of Agriculture, Tokyo, Japan.Department of Bioscience, Tokyo University of Agriculture, Tokyo, Japan.Department of Molecular Microbiology, Tokyo University of Agriculture, Tokyo, Japan.Research Institute of Green Science and Technology, Shizuoka University, Shizuoka, Japan.NODAI Genome Research Center, Tokyo University of Agriculture, Tokyo, Japan.Department of Bioscience, Tokyo University of Agriculture, Tokyo, Japan.Graduate School of Medical Life Science, Yokohama City University, Yokohama, Japan.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32603360

Citation

Kasahara, Koji, et al. "Fpr1, a Primary Target of Rapamycin, Functions as a Transcription Factor for Ribosomal Protein Genes Cooperatively With Hmo1 in Saccharomyces Cerevisiae." PLoS Genetics, vol. 16, no. 6, 2020, pp. e1008865.
Kasahara K, Nakayama R, Shiwa Y, et al. Fpr1, a primary target of rapamycin, functions as a transcription factor for ribosomal protein genes cooperatively with Hmo1 in Saccharomyces cerevisiae. PLoS Genet. 2020;16(6):e1008865.
Kasahara, K., Nakayama, R., Shiwa, Y., Kanesaki, Y., Ishige, T., Yoshikawa, H., & Kokubo, T. (2020). Fpr1, a primary target of rapamycin, functions as a transcription factor for ribosomal protein genes cooperatively with Hmo1 in Saccharomyces cerevisiae. PLoS Genetics, 16(6), e1008865. https://doi.org/10.1371/journal.pgen.1008865
Kasahara K, et al. Fpr1, a Primary Target of Rapamycin, Functions as a Transcription Factor for Ribosomal Protein Genes Cooperatively With Hmo1 in Saccharomyces Cerevisiae. PLoS Genet. 2020;16(6):e1008865. PubMed PMID: 32603360.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Fpr1, a primary target of rapamycin, functions as a transcription factor for ribosomal protein genes cooperatively with Hmo1 in Saccharomyces cerevisiae. AU - Kasahara,Koji, AU - Nakayama,Risa, AU - Shiwa,Yuh, AU - Kanesaki,Yu, AU - Ishige,Taichiro, AU - Yoshikawa,Hirofumi, AU - Kokubo,Tetsuro, Y1 - 2020/06/30/ PY - 2019/08/27/received PY - 2020/05/15/accepted PY - 2020/07/13/revised PY - 2020/7/1/pubmed PY - 2020/7/1/medline PY - 2020/7/1/entrez SP - e1008865 EP - e1008865 JF - PLoS genetics JO - PLoS Genet. VL - 16 IS - 6 N2 - Fpr1 (FK506-sensitive proline rotamase 1), a protein of the FKBP12 (FK506-binding protein 12 kDa) family in Saccharomyces cerevisiae, is a primary target for the immunosuppressive agents FK506 and rapamycin. Fpr1 inhibits calcineurin and TORC1 (target of rapamycin complex 1) when bound to FK506 and rapamycin, respectively. Although Fpr1 is recognised to play a crucial role in the efficacy of these drugs, its physiological functions remain unclear. In a hmo1Δ (high mobility group family 1-deleted) yeast strain, deletion of FPR1 induced severe growth defects, which could be alleviated by increasing the copy number of RPL25 (ribosome protein of the large subunit 25), suggesting that RPL25 expression was affected in hmo1Δfpr1Δ cells. In the current study, extensive chromatin immunoprecipitation (ChIP) and ChIP-sequencing analyses revealed that Fpr1 associates specifically with the upstream activating sequences of nearly all RPG (ribosomal protein gene) promoters, presumably in a manner dependent on Rap1 (repressor/activator site binding protein 1). Intriguingly, Fpr1 promotes the binding of Fhl1/Ifh1 (forkhead-like 1/interacts with forkhead 1), two key regulators of RPG transcription, to certain RPG promoters independently of and/or cooperatively with Hmo1. Furthermore, mutation analyses of Fpr1 indicated that for transcriptional function on RPG promoters, Fpr1 requires its N-terminal domain and the binding surface for rapamycin, but not peptidyl-prolyl isomerase activity. Notably, Fpr1 orthologues from other species also inhibit TORC1 when bound to rapamycin, but do not regulate transcription in yeast, which suggests that these two functions of Fpr1 are independent of each other. SN - 1553-7404 UR - https://www.unboundmedicine.com/medline/citation/32603360/Fpr1,_a_primary_target_of_rapamycin,_functions_as_a_transcription_factor_for_ribosomal_protein_genes cooperatively_with_Hmo1_in_Saccharomyces_cerevisiae L2 - https://dx.plos.org/10.1371/journal.pgen.1008865 DB - PRIME DP - Unbound Medicine ER -
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