Abstract
While NF90 has been known to participate in transcription, translation and microRNA biogenesis, physiological functions of this protein still remain unclear. To uncover this, we generated transgenic (Tg) mice using NF90 cDNA under the control of β-actin promoter. The NF90 Tg mice exhibited a reduction in body weight compared with wild-type mice, and a robust expression of NF90 was detected in skeletal muscle, heart and eye of the Tg mice. To evaluate the NF90 overexpression-induced physiological changes in the tissues, we performed a number of analyses including CT-analysis and hemodynamic test, revealing that the NF90 Tg mice developed skeletal muscular atrophy and heart failure. To explore causes of the abnormalities in the NF90 Tg mice, we performed histological and biochemical analyses for the skeletal and cardiac muscles of the Tg mice. Surprisingly, these analyses demonstrated that mitochondria in those muscular tissues of the Tg mice were degenerated by autophagy. To gain further insight into the cause for the mitochondrial degeneration, we identified NF90-associated factors by peptide mass fingerprinting. Of note, approximately half of the NF90-associated complexes were ribosome-related proteins. Interestingly, protein synthesis rate was significantly suppressed by high-expression of NF90. These observations suggest that NF90 would negatively regulate the function of ribosome via its interaction with the factors involved in the ribosome function. Furthermore, we found that the translations or protein stabilities of PGC-1 and NRF-1, which are critical transcription factors for expression of mitochondrial genes, were significantly depressed in the skeletal muscles of the NF90 Tg mice. Taken together, these findings suggest that the mitochondrial degeneration engaged in the skeletal muscle atrophy and the heart failure in the NF90 Tg mice may be caused by NF90-induced posttranscriptional repression of transcription factors such as PGC-1 and NRF-1 for regulating nuclear-encoded genes relevant to mitochondrial function.
Highlights
A group of double-stranded RNA binding proteins (DRBPs) numbering more than 15 plays key roles in transcription, translation, mRNA processing, transportation, stability and/or editing, and microRNA biogenesis [1,2]
We examined whether expression levels of mitochondrial genes including cytochrome c oxidase (COX) -2, COX-4 and nuclear respiratory factor-1 (NRF-1), which are downstream targets of PGC-1, are altered in the skeletal muscles of the nuclear factor 90 (NF90) Tg mice
Further analysis revealed that the NF90 Tg mice exhibited skeletal muscular atrophy and heart failure accompanied with mitochondrial vacuolation which is caused by autophagocytosis (Figure 2, 3, 4, 5 and S3)
Summary
A group of double-stranded (ds) RNA binding proteins (DRBPs) numbering more than 15 plays key roles in transcription, translation, mRNA processing, transportation, stability and/or editing, and microRNA (miRNA) biogenesis [1,2]. The dsRBM is evolutionarily conserved from Escherichia coli (ribonuclease RNASE-III) through Saccharomyces cerevisiae (RNASE-III) and Drosophila melanogaster (Staufen), to humans (protein kinase activated by dsRNA (PKR), and TAR RNA binding protein (TRBP) among others) and contributes to binding to DNA or RNA metabolites at the DRBPs involved in multiple cellular events described above. One such DRBPs is nuclear factor 90 (NF90) ( referred to NFAR1 or DRBP76), which is conserved among human, mouse, rat and Xenopus [1]. In addition to roles in transcription and miRNA biogenesis, it has been reported that NF90 participates in RNA splicing [10], mRNA stability and/or transportation [11,12,13], translation [14] and regulation of virus replication [15]
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