HGNC Approved Gene Symbol: PNRC2
Cytogenetic location: 1p36.11 Genomic coordinates (GRCh38): 1:23,959,164-23,963,462 (from NCBI)
Using the N-terminal activator function-1 (AF1) domain of mouse estrogen-related receptor-gamma (ESRRG; 602969) isoform-2 (ESRRG2) as bait in a yeast 2-hybrid screen of a human brain cDNA library, Hentschke and Borgmeyer (2003) cloned full-length PNRC2. The deduced 139-amino acid protein has a calculated molecular mass of 16 kD. Northern blot analysis detected transcripts of 2.9 and 1.9 kb. Highest expression was in kidney, heart, skeletal muscle, and placenta, with weaker expression in other tissues examined.
By immunohistochemical analysis of HeLa cells, Cho et al. (2009) showed that PNRC2 localized to processing bodies (P bodies), the sites of nonsense-mediated mRNA decay (NMD). A portion of endogenous PNRC2 was also detected in the nucleus.
Using a protein pull-down assay, Hentschke and Borgmeyer (2003) confirmed interaction between human PNRC2 and mouse Esrrg2. Coexpression of PNRC2 and Esrrg2 in simian kidney cells resulted in increased reporter gene activity compared with that shown by Esrrg2 alone. PNRC2 alone did not stimulate reporter gene activity. Mutation analysis showed that the AF1 domain of Esrrg2 was required for PNRC2-dependent transactivation.
Cycles of UPF1 (601430) phosphorylation and dephosphorylation are essential for efficient NMD. Cho et al. (2009) showed that PNRC2 interacted with UPF1 in a yeast 2-hybrid screen of a human thymus cDNA library. Coimmunopurification analysis and protein pull-down assays confirmed the interaction. PNRC2 preferentially interacted with hyperphosphorylated UPF1 and triggered movement of UPF1 into P bodies. Downregulation of PNRC2 impaired the localization of hyperphosphorylated UPF1 to P bodies. PNRC2 also interacted with DCP1A (607010), a component of the decapping complex. Downregulation of endogenous PNRC2 or UPF1 in HeLa cells via small interfering RNA abrogated NMD and increased the levels of COMMD7 and IARS (600709) mRNA, suggesting that these are natural NMD substrates. Furthermore, PNRC2 elicited mRNA degradation when tethered to RNA downstream of the normal termination codon. Cho et al. (2009) concluded that PNRC2 plays an essential role in NMD, mediating the interaction between the NMD machinery and the decapping complex, and targets aberrant mRNAs to P bodies.
Hartz (2008) mapped the PNCR2 gene to chromosome 1p36.11 based on an alignment of the PNCR2 sequence (GenBank AF151042) with the genomic sequence (build 36.1).
Zhou et al. (2008) found that Pnrc2-null mice were viable and fertile. However, Pnrc2-null mice, especially males, were lean and resistant to high fat diet-induced obesity without induction of insulin resistance. Pnrc2-null male mice had a higher metabolic rate than wildtype mice, and they consumed more oxygen and produced more heat. Consistent with reduced adipose mass, the levels of leptin (LEP; 164160) were lower in Pnrc2-null mice. Zhou et al. (2008) concluded that PNRC2 plays a role in controlling the balance between energy storage and expenditure.
Cho, H., Kim, K. M., Kim, Y. K. Human proline-rich nuclear receptor coregulatory protein 2 mediates an interaction between mRNA surveillance machinery and decapping complex. Molec. Cell 33: 75-86, 2009. [PubMed: 19150429] [Full Text: https://doi.org/10.1016/j.molcel.2008.11.022]
Hartz, P. A. Personal Communication. Baltimore, Md. 3/7/2008.
Hentschke, M., Borgmeyer, U. Identification of PNRC2 and TLE1 as activation function-1 cofactors of the orphan nuclear receptor ERR-gamma. Biochem. Biophys. Res. Commun. 312: 975-982, 2003. [PubMed: 14651967] [Full Text: https://doi.org/10.1016/j.bbrc.2003.11.025]
Zhou, D., Shen, R., Ye, J. J., Li, Y., Tsark, W., Isbell, D., Tso, P., Chen, S. Nuclear receptor coactivator PNRC2 regulates energy expenditure and adiposity. J. Biol. Chem. 283: 541-553, 2008. [PubMed: 17971453] [Full Text: https://doi.org/10.1074/jbc.M703234200]