Abstract
Cytoplasmic localization, stability, and translation of mRNAs are controlled by their dynamic association of numerous mRNA-binding (mRNP) proteins, including cold shock domain (CSD)-containing proteins, heterogeneous nuclear ribonucleoproteins (hnRNPs), and serine/arginine-rich (SR) proteins. Here, we demonstrate that the most abundant human mRNP protein, the CSD-containing Y-box-binding protein 1 (YBX1), the closely related YBX3 protein, and other mRNP proteins, such as SRSF1, SRSF2, SRSF3, hnRNP A1, and H, specifically and efficiently interact with overlapping sets of mitochondrial tRNAs (mt tRNAs). In vitro reconstitution and in vivo binding experiments show that YBX1 recognizes the D- and/or T-stem–loop regions of mt tRNAs through relying on the RNA-binding capacity of its CSD. Cell fractionation and in vivo RNA–protein cross-linking experiments demonstrate that YBX1 and YBX3 interact with mt tRNAs in the cytosol outside of mitochondria. Cell fractionation and fluorescence in situ hybridization experiments provide evidence that mitochondrial autophagy promotes the release of mt tRNAs from the mitochondria into the cytoplasm. Association of mRNP proteins with mt tRNAs is highly dynamic; it is rapidly increased upon transcription inhibition and decreased during apoptosis. Although the cytoplasmic function of mt tRNAs remains elusive, their dynamic interactions with key mRNA-binding proteins may influence cytoplasmic mRNA stability and/or translation.
Highlights
Human Y-box-binding proteins Y-box-binding protein 1 (YBX1), YBX3, and the germ cell–specific YBX2 belong to the superfamily of cold shock domain (CSD) proteins (Wolffe et al 1992; Graumann and Marahiel 1998)
We demonstrate that a fraction of human HeLa mt tRNAs accumulate in the cytoplasm where they interact with abundant mRNP proteins, including the YBX1 and YBX3 CSD proteins, the SRSF1, SRSF2, and SRSF3 SR proteins, and the heterogeneous nuclear ribonucleoproteins (hnRNPs) A1 and H proteins
YBX1 and YBX3 interact with mt tRNAs in the cytosol outside of mitochondria
Summary
Human Y-box-binding proteins YBX1, YBX3, and the germ cell–specific YBX2 belong to the superfamily of cold shock domain (CSD) proteins (Wolffe et al 1992; Graumann and Marahiel 1998). Together with numerous hnRNP proteins and serine/arginine-rich (SR) proteins, YBX1 and YBX3 bind to the newly synthesized precursor mRNAs (pre-mRNAs). They regulate pre-mRNA splicing and polyadenylation, promote mRNA export to the cytoplasm, and control cytoplasmic mRNA translation, stability, and localization (Eliseeva et al 2011; Lyabin et al 2014; Singh et al.2015). Dynamic association of YBX1 with mRNAs controls the cytoplasmic stability and translation of a large set of mRNAs (Evdokimova et al 1998, 2006; Lyabin et al 2014). Cytoplasmic (cyt) tRNA fragments (tRFs) produced by stress-activated angiogenin have been found to possess high affinity to YBX1 and have been demonstrated to destabilize YBX1-associated mRNAs by competitively displacing them from YBX1 (Goodarzi et al 2015)
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