The Oncogene eIF4E Reprograms the Nuclear Pore Complex to Promote mRNA Export and Oncogenic Transformation

Abstract

The eukaryotic translation initiation factor eIF4E is a potent oncogene that promotes the nuclear export and translation of specific transcripts. Here, we discovered that eIF4E alters the cytoplasmic face of the nuclear pore complex (NPC) which leads to enhanced mRNA export of eIF4E target mRNAs. Specifically, eIF4E substantially reduces the major component of the cytoplasmic fibrils of the NPC, RanBP2, relocalizes an associated nucleoporin Nup214, and elevates RanBP1 and the RNA export factors, Gle1 and DDX19. Genetic or pharmacological inhibition of eIF4E impedes these effects. RanBP2 overexpression specifically inhibits the eIF4E mRNA export pathway and impairs oncogenic transformation by eIF4E. The RanBP2 cytoplasmic fibrils likely slow the release/recycling of critical export factors to the nucleus. eIF4E overcomes this inhibitory mechanism by indirectly reducing levels of RanBP2. More globally, these studies suggest that reprogramming the NPC is a means by which oncogenes can harness the proliferative capacity of the cell.

Differential Loss of Prolyl Isomerase or Chaperone Activity of Ran-binding Protein 2 (Ranbp2) Unveils Distinct Physiological Roles of Its Cyclophilin Domain in Proteostasis

“…Another possibility is that CY of Ranbp2 causes the post-transcriptional down-regulation of M-opsin upon its aggregation because of the down-modulation of nucleocytoplasmic export, translation, or trafficking of M-opsin transcripts. To this effect, Ranbp2 is implicated in potentiating the translation of mRNA encoding secretory proteins or elF4E-mediated nuclear export and translation of selective transcripts (123,124). Neither of the scenarios described are mutually exclusive, and follow-up studies are needed to examine these mechanisms in greater depth.…”

“…Because we did not discern any ERG and hnRNPA2/B1 changes in the outer retina, the most likely scenario is that a decrease of hnRNPA2/B1 levels in the inner retina upon loss of Ranbp2 PPIase activity selectively potentiates the activity of hnRNPA2/B1 leading to a shorter dark-adapted VEP latency. Furthermore, the following observations also support the notion that changes in hnRNPA2/B1 proteostasis are a major contributor to the reduced latency of dark-adapted VEPs: (i) Ranbp2 is a docking site for the nuclear export receptor, CRM1/ exportin-1 (63); (ii) Ranbp2 affects selectively the levels of the RNA-binding proteins, hnRNPA2/B1, as shown here; (iii) Ranbp2 binds single-stranded RNA (126); and (iv) Ranbp2 stimulates the export of mRNA and translation of endoplasmic reticulum-targeted and likely mitochondrially targeted proteins in cell culture (123,124). Finally, although no PPIase activity was detected consistently in vitro with CY R2944A , it is arguably possible that Tg-Ranbp2 R2944A-HA ::Ranbp2 Ϫ/Ϫ mice may still harbor vanishingly low levels of CY PPIase activity.…”

A biochemical framework for eIF4E-dependent mRNA export and nuclear recycling of the export machinery

“…In this way, LRPPRC acts as a major component of the export machinery, interacting with eIF4E, target RNAs, and CRM1. eIF4E overexpression leads to many alterations to the nuclear pore complex related to CRM1, which likely facilitate the release of RNA cargoes from this receptor once on the cytoplasmic side (Culjkovic-Kraljacic et al 2012).…”

“…Mutagenesis studies also support a role for eIF4E mRNA export activity in transformation. For instance, the S53A eIF4E mutant does not act in mRNA export or transform cells; however, this mutant still binds the cap and is active in translation in the cytoplasm (Kaufman et al 1993;Cohen et al 2001;Culjkovic-Kraljacic et al 2012). In the nuclei of mammalian cells, eIF4E specifically associates with over 3000 mRNAs .…”

227 Luzp4 defines a new mRNA export pathway in cancer cells

“…These proteins include eIF4E which is up-regulated in ∼30% of cancer cells. eIF4E is required for the export of specific transcripts via the CRM1 pathway and also remodels the nuclear pore complex which promotes mRNA export and oncogenic transformation (20). The TREX subunit Thoc5 is the target of leukaemogenic tyrosine kinases (21) and two other TREX subunits, Thoc1 (Hpr1) and Alyref, are dysregulated in cancer cells (22)(23)(24).…”