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Review
. 2015 May:479-480:457-74.
doi: 10.1016/j.virol.2015.03.001. Epub 2015 Mar 26.

Nuclear proteins hijacked by mammalian cytoplasmic plus strand RNA viruses

Richard E Lloyd  1
Affiliations
Review

Nuclear proteins hijacked by mammalian cytoplasmic plus strand RNA viruses

Richard E Lloyd. Virology. 2015 May.

Abstract

Plus strand RNA viruses that replicate in the cytoplasm face challenges in supporting the numerous biosynthetic functions required for replication and propagation. Most of these viruses are genetically simple and rely heavily on co-opting cellular proteins, particularly cellular RNA-binding proteins, into new roles for support of virus infection at the level of virus-specific translation, and building RNA replication complexes. In the course of infectious cycles many nuclear-cytoplasmic shuttling proteins of mostly nuclear distribution are detained in the cytoplasm by viruses and re-purposed for their own gain. Many mammalian viruses hijack a common group of the same factors. This review summarizes recent gains in our knowledge of how cytoplasmic RNA viruses use these co-opted host nuclear factors in new functional roles supporting virus translation and virus RNA replication and common themes employed between different virus groups.

Keywords: Coronavirus; Enterovirus; Flavivirus; G3BP1; Hepatitis C virus; La protein; NSAP; Norovirus; PCBP2; PTB; Poliovirus; RNA helicase A; RNA virus; SRp20; Tia1/TIAR; UNR; hnRNP A1; hnRNP C; hnRNP K; hnRNP M.

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Figures

Fig. 1
Fig. 1
Cartoon illustrating roles of RBPs in PV replication. (A) PV Translation. Host factor PCBP binds both cloverleaf stem-loop B (SLB) and IRES SLIV, PTB binds SLV and together with La helps eIF4G and other canonical translation factors (not shown) bind properly to recruit ribosomes. ITAFs provide RNA chaperone functions and modular binding motifs link and fold different stem loops. Interactions of PABP with PCBP and PABP with initiation factors (eIF4G, eIF4B interactions not depicted) help close the RNA 5′-3′ loop and facilitate ribosomes recycling from stop codon to start codon. Other ITAFs for PV mentioned in the text are not depicted. (B) Switch to replication. Viral polymerase precursor 3CD binds 5′CL SLD, together with cleavage of PCBP, PTB and La by 3Cpro (scissors), converts the template to translation–initiation–incompetent state, plus blocks ribosome recycling and thus ribosomes runoff and clear the template. (C) PV minus strand replication. Replicase complex consisting of interacting 3CD–3Dpol complexes initiates replication. The complex is oriented properly via PCBP binding PABP. (D) PV plus strand replication. The double-stranded RF replication intermediate (nascent negative strand shown in red) breathes allowing cloverleaf and anti-cloverleaf to form, stabilized by binding PCBP and hnRNP C respectively. Polymerase replicase complex also builds on 5′ CL and initiates replication on negative strand template that is properly positioned for precise-end initiation. hnRNP C can also interact with SL on the 5′ end of the negative strand that also requires breathing to form. In this scenario PABP may be able to rebind to poly(A) tail and hnRNP oligomerization and PABP interaction with PCBP may facilitate genome circularization in double-stranded RF intermediate.
Fig. 2
Fig. 2
(A) Structural elements of flavivirus 5′ and 3′ UTRs based on Dengue virus sequences. Start and stop codons defining the open reading frame are shown. The 5′ UTR is ~95 nt and includes 5′ SLA, 5′ SLB. The flavivirus 3′ UTR is <380 nt and contains regions with conserved structural elements: VR (dark blue) with SL-I through IV, the 3′ DB region containing duplicate dumbbell structures (DB1 and DB2) (light blue) and the 3′ CS/SL region (red) containing the conserved 3′ SL. All structures from SL-1 through DB-2 participate in pseudoknots (not depicted). To facilitate translation poly(A)-binding protein binds A-rich sequences in the DB region allowing protein-bridge looping to translation factor eIF4G associated with the 5′ cap structure. YB-1 binds the 3′ SL and represses translation and replication. PTB and La bind 3′ UTR may also facilitate translation. (B) Long range interaction between complimentary sequences in 5′ and 3′ regions (5′ CS, 3′ CS; 5′ UAR, 3′ UAR) facilitate genomic looping associated with RNA replication. This looping remodels RNA into new conformations that may promote binding of additional host RBPs not associated with translating DENV RNA such as eEF1, and the dsRNA binding proteins NF90, NF45 and RHA that bind the 3′ SL. In HCV, NF90 binds both 5′ and 3′ UTR of HCV RNA and RHA is involved in bridging 5′ and 3′ UTRs (not depicted). A similar arrangement may exist in flaviviruses where NF90 and RHA may also bind 5′ UTR stem loops and stabilize the looped structure to promote negative strand RNA replication. The NS5 RdRp binds to the 5′ SL1 which due to looping helps position the polymerase near the 3′ terminus (Bidet and Garcia-Blanco, 2014). NS5 may also be recruited by La, which binds the 5′ UTR.
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