Heterogeneous nuclear ribonucleoproteins (hnRNPs) in cellular processes: Focus on hnRNP E1's multifunctional regulatory roles

Abstract

Heterogeneous nuclear ribonucleoproteins (hnRNPs) comprise a family of RNA-binding proteins. The complexity and diversity associated with the hnRNPs render them multifunctional, involved not only in processing heterogeneous nuclear RNAs (hnRNAs) into mature mRNAs, but also acting as trans-factors in regulating gene expression. Heterogeneous nuclear ribonucleoprotein E1 (hnRNP E1), a subgroup of hnRNPs, is a KH-triple repeat containing RNA-binding protein. It is encoded by an intronless gene arising from hnRNP E2 through a retrotransposition event. hnRNP E1 is ubiquitously expressed and functions in regulating major steps of gene expression, including pre-mRNA processing, mRNA stability, and translation. Given its wide-ranging functions in the nucleus and cytoplasm and interaction with multiple proteins, we propose a post-transcriptional regulon model that explains hnRNP E1's widespread functional diversity.

FIGURE 1.

Structure of hnRNP proteins. (A) The RNP-CS-RBD motif has a βαββαβ structure. The octameric RNP1 and hexameric RNP2 sequences are juxtaposed on β3 and β1, respectively. The structure shown is of multiple isomorphous replacement (MIR) of two RBDs of human hnRNP A1 at 1.75 Å (PDB ID: 1HA1) (Shamoo et al. 1997). (B) The KH domain comprises a triple β-sheet platform supporting three α-helical segments. Structure shown is of X-ray crystallography (resolution 3 Å) of KH1 domain (2-polymer) of human hnRNP E1 (PBD ID: 1ZTG) (Sidiqi et al. 2005). Both structures have been derived by the JMol algorithm.

FIGURE 2.

Post-transcriptional regulation by hnRNP E1 during development and differentiation. hnRNP E1 alone, or in combination with other hnRNPs, modulates mRNA stability of α-globin (A) or the translation of 15-LOX (B) or Dab2 (C) mRNAs. The regulatory mechanism involves binding to putative cis elements in the 3′-UTRs, which in most cases is disrupted by phosphorylation of one or more of the bound hnRNP proteins. A brief description of each regulatory mechanism is given. (15-LOX) 15-lipoxygenase; (DICE) differentiation control element; (BAT) TGFβ-activated translation element; (Dab2) disabled-2; (ILEI) interleukin-like EMT inducer.

FIGURE 3.

Post-transcriptional regulons potentiate functional diversity of hnRNP E1. Putative cis elements in the 3′-UTRs of target transcripts, untranslated sequence elements for regulation (USER) codes, determine the content of the mRNP complex that will form. Many USER codes, such as DICE, BAT, and CARE, have been defined in mediating post-transcriptional regulation. and one transcript can harbor more than one USER code. hnRNP E1 and other hnRNPs bind alone or as a multifactorial mRNP complex to USER codes and give rise to post-transcriptional regulons. This model takes into account the multifunctional, yet conserved, diversity of hnRNP E1. As shown here, hnRNP E1 binding to other proteins and specific USER codes, BAT, DICE, or CARE elements, dictates their subsequent function during differentiation, EMT, and development. (BAT) TGFβ-activated translation element; (DICE) differentiation control element; (CARE) CACA-rich elements that bind hnRNP L.