Diverse roles of host RNA binding proteins in RNA virus replication

Abstract

Plus-strand +RNA viruses co-opt host RNA-binding proteins (RBPs) to perform many functions during viral replication. A few host RBPs have been identified that affect the recruitment of viral +RNAs for replication. Other subverted host RBPs help the assembly of the membrane-bound replicase complexes, regulate the activity of the replicase and control minus- or plus-strand RNA synthesis. The host RBPs also affect the stability of viral RNAs, which have to escape cellular RNA degradation pathways. While many host RBPs seem to have specialized functions, others participate in multiple events during infection. Several conserved RBPs, such as eEF1A, hnRNP proteins and Lsm 1-7 complex, are co-opted by evolutionarily diverse +RNA viruses, underscoring some common themes in virus-host interactions. On the other hand, viruses also hijack unique RBPs, suggesting that +RNA viruses could utilize different RBPs to perform similar functions. Moreover, different +RNA viruses have adapted unique strategies for co-opting unique RBPs. Altogether, a deeper understanding of the functions of the host RBPs subverted for viral replication will help development of novel antiviral strategies and give new insights into host RNA biology.

Figure 1

A model of the roles of host RBPs in PV replication. (A) The roles of host RBPs in PV translation. The binding of host RBPs to stem-loop IV of internal ribosomal entry site (IRES, shown as stem-loop structures) is essential for cap-independent translation of PV genome. (B) The roles of host RBPs in a switch by the PV RNA from translation to replication. The dual roles of PCBP2 in PV translation and replication place PCBP2 in an ideal position to mediate the switch from translation to replication. The viral 3CD likely serves as a “sensor” to measure viral protein translation, while PCBP2 acts as a “molecular switch”. The involvement of PCBP2 in PV replication is facilitated by the proteolytic cleavage of PCBP2 by the viral protease 3C/3CD during the mid-to-late phase of infection. (C) The roles of host RBPs in PV RNA replication. PCBP interacts with the 5′ cloverleaf structure and forms RNP with polymerase precursor 3CD protein to promote initiation of (−)RNA synthesis. The replication initiation complex formed at 5′-UTR, which contains the viral 3D^pol RdRp (either activated via a cleavage of the 3CD precursor to yield the matured 3D^pol or via direct recruitment of 3D^pol), is brought to 3′-end by genome circularization via interaction of PCBP with PABP bound to the poly(A)-sequence in the 3′-UTR. hnRNP C has been proposed to maintain the single-stranded form of the 3′-end of PV (−)RNA via its RNA chaperone activity, and then, recruit viral 3CD replication protein to form an initiation complex for (+)RNA synthesis. Since hnRNP C interacts with both termini of PV (−)RNA, hnRNP oligomerization could bring the 5′- and 3′-end sequences into proximity, thus facilitating initiation of (+)RNA synthesis. The detailed functions of the RBPs and viral factors are described in the text.

Figure 2

Comparison of the co-opted host factors for Qbeta bacteriophage and TBSV replication. (A) The long-range interactions between regions in the Qbeta (+)RNA genome are depicted by multiple lines. The detailed functions of the RBPs and viral factors are described in the text. (B) The long-range base-pairing in the TBSV (+)RNA genome brings recruitment element bound by p33 into the vicinity of the 3′-UTR, which also has base-pairing between the silencer element and the 3′ end as depicted by multiple lines. The shown RBPs facilitate TBSV RNA synthesis as described in the text.