期刊
NUCLEIC ACIDS RESEARCH
卷 50, 期 4, 页码 2172-2189出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkac086
关键词
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资金
- Centre National de la Recherche Scientifique
- Universite de Lorraine
- Ministere de l'Enseignement Superieur, de la Recherche et de l'Innovation MESRI
- Ligue contre le Cancer
- ANRS [20413 AO 2020-2 CSS 11, ECTZ133498, AO 2022-1 CSS 11, ECTZ188028]
- Universite de Lorraine [CS-UL 2018 AAP-BMS 003 162 INCITATIF IMoPA Rederstorff M]
In this study, it was found that the R2TP component RPAP3 binds to TRBP rather than PACT, and the binding of TRBP to RPAP3 or Dicer is mutually exclusive. Additionally, it was discovered that AGO(1/2), TRBP, and Dicer are all sensitive to HSP90 inhibition, with increased sensitivity of TRBP in the absence of RPAP3. Furthermore, RPAP3 appears to impede miRNA activity, suggesting that the R2TP chaperone might sequester TRBP to regulate the miRNA pathway.
MicroRNAs silence mRNAs by guiding the RISC complex. RISC assembly occurs following cleavage of pre-miRNAs by Dicer, assisted by TRBP or PACT, and the transfer of miRNAs to AGO proteins. The R2TP complex is an HSP90 co-chaperone involved in the assembly of ribonucleoprotein particles. Here, we show that the R2TP component RPAP3 binds TRBP but not PACT. The RPAP3-TPR1 domain interacts with the TRBP-dsRBD3, and the 1.5 angstrom resolution crystal structure of this complex identifies key residues involved in the interaction. Remarkably, binding of TRBP to RPAP3 or Dicer is mutually exclusive. Additionally, we found that AGO(1/2), TRBP and Dicer are all sensitive to HSP90 inhibition, and that TRBP sensitivity is increased in the absence of RPAP3. Finally, RPAP3 seems to impede miRNA activity, raising the possibility that the R2TP chaperone might sequester TRBP to regulate the miRNA pathway.
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