hnRNP E1 and E2 have distinct roles in modulating HIV-1 gene expression

Abstract

Pre-mRNA processing, including 5' end capping, splicing, and 3' end cleavage/polyadenylation, are events coordinated by transcription that can influence the subsequent export and translation of mRNAs. Coordination of RNA processing is crucial in retroviruses such as HIV-1, where inefficient splicing and the export of intron-containing RNAs are required for expression of the full complement of viral proteins. RNA processing can be affected by both viral and cellular proteins, and in this study we demonstrate that a member of the hnRNP E family of proteins can modulate HIV-1 RNA metabolism and expression. We show that hnRNP E1/E2 are able to interact with the ESS3a element of the bipartite ESS in tat/rev exon 3 of HIV-1 and that modulation of hnRNP E1 expression alters HIV-1 structural protein synthesis. Overexpression of hnRNP E1 leads to a reduction in Rev, achieved in part through a decrease in rev mRNA levels. However, the reduction in Rev levels cannot fully account for the effect of hnRNP E1, suggesting that hmRNP E1 might also act to suppress viral RNA translation. Deletion mutagenesis determined that the C-terminal end of hnRNP E1 was required for the reduction in Rev expression and that replacing this portion of hnRNP E1 with that of hnRNP E2, despite the high degree of conservation, could not rescue the loss of function.

The Poly(C) Binding Protein Pcbp2 and Its Retrotransposed Derivative Pcbp1 Are Independently Essential to Mouse Development

“…A number of ex vivo models support distinct biochemical functions for Pcbp1 and Pcbp2. For example, Pcbp1 is uniquely capable of regulating epithelial-mesenchymal transitions and stabilizing vascular nitric oxide synthase transcripts (37,42,70), while Pcbp2 specifically controls tumor suppressor genes in chronic myelogenous leukemia, poliovirus translation, and HIV gene expression (39)(40)(41). Thus, our in vivo analysis of embryogenesis is concordant with previous ex vivo studies in demonstrating that Pcbp1 and Pcbp2 play distinct roles in organism function.…”

“…Importantly, current evidence also suggests that these proteins may have acquired a subset of nonredundant functions. For example, unique functions of Pcbp2 have been demonstrated in HIV gene expression, poliovirus translation, and tumor suppressor gene expression in chronic myelogenous leukemia (39)(40)(41). Mechanistic support for Pcbp1-specific functions in development and in response to physiologic stimuli comes from studies of epithelial-mesenchymal transitions (EMT) in secretory epithelium where Pcbp1 has been demonstrated to regulate translational silencing of EMT genes in response to transforming growth factor ␤ (TGF-␤) signaling (42,43).…”

Poly(C)-binding protein 1 (PCBP1) mediates housekeeping degradation of mitochondrial antiviral signaling (MAVS)

“…The unique property of PCBP1 was observed in knockdown studies that point to a housekeeping role for PCBP1 at the quiescent state ( Figure 6). This specificity may serve as another sound piece of evidence for divergent physiological functions of the two proteins as reported elsewhere [40][41][42][43].…”

Incrimination of Heterogeneous Nuclear Ribonucleoprotein E1 (hnRNP-E1) as a Candidate Sensor of Physiological Folate Deficiency

“…FR also functions in murine cells (4,5,60,61), and mice have a similar regulatory unit involving the interaction between a 17-base cis-element in the 5Ј-UTR of FR mRNA and a transfactor called mouse poly(rC)-binding protein (␣CP1), which is homologous with human hnRNP-E1 and found in several murine tissues, including the brain (12,52,62,63). Based on our data on the interaction of homocysteinylated hnRNP-E1 with mRNA cis-elements from TH (45) and NF-M (31, 64 -67), it is plausible that homocysteinylation of hnRNP-E1 within murine tissues can also trigger the binding of several diverse mRNAs with common signature poly(rC)-rich or poly(U)-rich sequences (18,20,31,38,40,43,47,48,58,68,69) that are part of a nutrition-sensitive (homocysteine-responsive), posttranscriptional RNA operon in mice.…”