Picornaviruses and nuclear functions: targeting a cellular compartment distinct from the replication site of a positive-strand RNA virus

Abstract

The compartmentalization of DNA replication and gene transcription in the nucleus and protein production in the cytoplasm is a defining feature of eukaryotic cells. The nucleus functions to maintain the integrity of the nuclear genome of the cell and to control gene expression based on intracellular and environmental signals received through the cytoplasm. The spatial separation of the major processes that lead to the expression of protein-coding genes establishes the necessity of a transport network to allow biomolecules to translocate between these two regions of the cell. The nucleocytoplasmic transport network is therefore essential for regulating normal cellular functioning. The Picornaviridae virus family is one of many viral families that disrupt the nucleocytoplasmic trafficking of cells to promote viral replication. Picornaviruses contain positive-sense, single-stranded RNA genomes and replicate in the cytoplasm of infected cells. As a result of the limited coding capacity of these viruses, cellular proteins are required by these intracellular parasites for both translation and genomic RNA replication. Being of messenger RNA polarity, a picornavirus genome can immediately be translated upon entering the cell cytoplasm. However, the replication of viral RNA requires the activity of RNA-binding proteins, many of which function in host gene expression, and are consequently localized to the nucleus. As a result, picornaviruses disrupt nucleocytoplasmic trafficking to exploit protein functions normally localized to a different cellular compartment from which they translate their genome to facilitate efficient replication. Furthermore, picornavirus proteins are also known to enter the nucleus of infected cells to limit host-cell transcription and down-regulate innate antiviral responses. The interactions of picornavirus proteins and host-cell nuclei are extensive, required for a productive infection, and are the focus of this review.

Additive Promotion of Viral Internal Ribosome Entry Site-Mediated Translation by Far Upstream Element-Binding Protein 1 and an Enterovirus 71-Induced Cleavage Product

“…Most of these cellular factors originally reside in the nucleus, and picornavirus infection subsequently forces them to redistribute from the nucleus to the cytoplasm [24]. In order to achieve this, picornaviruses disrupt nuclear pore complexes (NPC) via cleavage of specific nuclear pore complex proteins (Nups) [48–52], such as Nup153, Nup98, and Nup62, and this disables key nuclear import and export pathways, thereby allowing the redistribution of nuclear-resident ITAFs [23], including nuclear factor FBP1 [21].…”

“…The coding limitations of their small viral genomes have led picornaviruses to evolve mechanisms for the exploitation of host factors to facilitate viral protein translation and genome replication, and therefore many host proteins are recruited as ITAFs that can interact with the viral IRES and modulate IRES-driven translation. For example, members of the heterogeneous ribonucleoprotein (hnRNP) family such as polypyrimidine tract-binding protein (PTB) [15, 16], poly(rC)-binding protein 2 (PCBP2) [17–19], AU-rich element binding factor 1 (AUF1) [20], and the cellular nuclear proteins, far upstream element-binding protein 1 (FBP1) and 2 (FBP2) [21, 22], have all been found to act as ITAFs that regulate IRES activity via direct binding to distinct regions of the 5′ UTR [23, 24]. …”

Host MicroRNA miR-197 Plays a Negative Regulatory Role in the Enterovirus 71 Infectious Cycle by Targeting the RAN Protein

“…Several host nuclear proteins are involved in the EV71 replication cycle, many of which, such as the far-upstream-elementbinding protein 1 and hnRNP K, relocalize from the nucleus to the cytoplasm during viral infection (27,31,32). The exact mechanisms underlying this redistribution might involve aberrant nuclear trafficking via the virus-induced cleavage of nuclear pore complex components (32).…”

“…We chose RAN for further study because several host nuclear proteins implicated in the EV71 replication cycle relocalize aberrantly from the nucleus to the cytoplasm during viral infection (27,31,32). Moreover, 3D of the 3CD precursor protein bears a classical simple basic NLS and is capable of entering the nucleus in PV-infected cells (33).…”

A novel passerivirus (family Picornaviridae) in an outbreak of enteritis with high mortality in estrildid finches (Uraeginthus sp.)

“…Among picornavirus proteins, the leader (L) protein shows the greatest diversity, both in function and in size [11,12]. More than half of the known members of picornavirus genera encode a leader (L) protein at the 5'end of the ORF (http://www.picornaviridae.com), but only a few of them have a known function [41][42][43][44][45].…”