KSRP-PMR1-exosome association determines parathyroid hormone mRNA levels and stability in transfected cells.
BACKGROUND
Parathyroid hormone (PTH) gene expression is regulated post-transcriptionally through the binding of the trans-acting proteins AU rich binding factor 1 (AUF1), Upstream of N-ras (Unr) and KH-type splicing regulatory protein (KSRP) to an AU rich element (ARE) in PTH mRNA 3'-UTR. AUF1 and Unr stabilize PTH mRNA while KSRP, recruiting the exoribonucleolytic complex exosome, promotes PTH mRNA decay.


RESULTS
PTH mRNA is cleaved by the endoribonuclease polysomal ribonuclease 1 (PMR1) in an ARE-dependent manner. Moreover, PMR1 co-immunoprecipitates with PTH mRNA, the exosome and KSRP. Knock-down of either exosome components or KSRP by siRNAs prevents PMR1-mediated cleavage of PTH mRNA.


CONCLUSIONS
PTH mRNA is a target for the endonuclease PMR1. The PMR1 mediated decrease in PTH mRNA levels involves the PTH mRNA 3'-UTR ARE, KSRP and the exosome. This represents an unanticipated mechanism by which the decay of an ARE-containing mRNA is facilitated by KSRP and is dependent on both the exosome and an endoribonuclease.
Nechama
Morris
M
Minerva Center for Calcium and Bone Metabolism, Nephrology Services, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Peng
Yong
Y
Bell
Osnat
O
Briata
Paola
P
Gherzi
Roberto
R
Schoenberg
Daniel R
DR
Naveh-Many
Tally
T
D020413:3' Untranslated Regions; D000252:Calcium-Transporting ATPases / Q000378:metabolism*; D002460:Cell Line; D055354:Exosomes / Q000378:metabolism*; D006801:Humans; D010281:Parathyroid Hormone / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D014162:Transfection
D020413:3' Untranslated Regions; C105789:KHSRP protein, human; D010281:Parathyroid Hormone; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D015534:Trans-Activators; C403624:ATP2C1 protein, human; D000252:Calcium-Transporting ATPases