Protor-2 interacts with tristetraprolin to regulate mRNA stability during stress.
The A/U-rich RNA-binding protein tristetraprolin (TTP) is an mRNA destabilizing factor which plays a role in the regulated turnover of many transcripts encoding proteins involved in immune function and cell growth control. TTP also plays a role in stress-induced destabilization of mRNAs. Here we report the interaction of TTP with ... a component of the mTORC2 kinase, Protor-2 (PRR5-L, protein Q6MZQ0/FLJ14213/CAE45978). Protor-2 is structurally similar to human PRR5 and has been demonstrated to bind mTORC2 via Rictor and/or Sin1 and may signal downstream events promoting apoptosis. Protor-2 dissociates from mTORC2 upon hyperactivation of the kinase and is not required for mTORC2 integrity or activity. We identified Protor-2 in a yeast two-hybrid screen as a TTP interactor using the C-terminal mRNA decay domain of TTP as bait. The interaction of Protor-2 with TTP was also confirmed in vivo in co-immunoprecipitation experiments and Protor-2 was also detected in immunoprecipitates of Rictor. Protor-2 was shown to stimulate TTP-mediated mRNA turnover of several TTP-associated mRNAs (TNF-α, GM-CSF, IL-3 and COX-2) in Jurkat cells when overexpressed while the half-lives of transcripts which do not decay via a TTP-mediated mechanism were unaffected. Knockdown of Protor-2 via RNAi inhibited TTP-mediated mRNA turnover of these TTP-associated mRNAs and inhibited association of TTP with cytoplasmic stress granules (SG) or mRNA processing bodies (P-bodies) following induction of the integrated stress response. These results suggest that Protor-2 associates with TTP to accelerate TTP-mediated mRNA turnover and functionally links the control of TTP-regulated mRNA stability to mTORC2 activity.
Mesh Terms:
Carrier Proteins, Cytoplasmic Granules, Gene Knockdown Techniques, HeLa Cells, Humans, Jurkat Cells, Protein Binding, Protein Interaction Domains and Motifs, RNA Interference, RNA Stability, RNA, Messenger, Recombinant Proteins, Stress, Physiological, Tristetraprolin, Two-Hybrid System Techniques
Carrier Proteins, Cytoplasmic Granules, Gene Knockdown Techniques, HeLa Cells, Humans, Jurkat Cells, Protein Binding, Protein Interaction Domains and Motifs, RNA Interference, RNA Stability, RNA, Messenger, Recombinant Proteins, Stress, Physiological, Tristetraprolin, Two-Hybrid System Techniques
Cell. Signal.
Date: Jan. 01, 2012
PubMed ID: 21964062
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