When Poly(A) Binding Proteins Meet Viral Infections, Including SARS-CoV-2

Abstract

Viruses have evolved diverse strategies to hijack the cellular gene expression system for their replication. The poly(A) binding proteins (PABPs), a family of critical gene expression factors, are viruses' common targets. PABPs act not only as a translation factor but also as a key factor of mRNA metabolism. During viral infections, the activities of PABPs are manipulated by various viruses, subverting the host translation machinery or evading the cellular antiviral defense mechanism. Viruses harness PABPs by modifying their stability, complex formation with other translation initiation factors, or subcellular localization to promote viral mRNAs translation while shutting off or competing with host protein synthesis. For the past decade, many studies have demonstrated the PABPs' roles during viral infection. This review summarizes a comprehensive perspective of PABPs' roles during viral infection and how viruses evade host antiviral defense through the manipulations of PABPs.

Keywords: host defense; poly(A)-binding protein (PABP); viral infection.

FIG 1

The structure of PABPs and translation initiation complex in uninfected cells. (A) The structure of different human PABPs. PABP comprises N-terminus RRM domains, C-terminus MLLE domain, and a proline-rich linker sequence connect these two parts. PABPC5 and PABPN1 do not have MLLE and the linker region. (B) The translation initiation complex in uninfected cells. PABPs bind to poly(A) tail eukaryotic cellular mRNA, and they guide 3′-end of mRNA to its 5′ cap through interaction with eIF4G. eIF4G is a bridge between the PABP-poly(A) tail and 5′ cap, forming a head-to-tail loop and recruiting ribosome 40S subunit for further translation initiations.

FIG 2

Cleavage of PABPs or eIF4G by viral proteases. (A) Cleavage of PABPs and eIF4G on the translation initiation complex by viral proteases. Viral 2A, 3C, and other viral proteases will cut PABPs from their RRM domains or proline-rich linker sequences when host cells are infected. This cleavage will lose the interaction between PABPs and eIF4G, leading to inhibition of cellular translation. Besides, viral protease (2A/3C/Lb proteases) will cleave eIF4G, separating its N-terminus from C-terminus, thus destabilizing PABPs interactions with poly(A) or disrupting eIF4G interaction with other translation initiation factors. (B) Schematic of the cleavage sites on PABPs and eIF4G by different viral proteases. The cleavage site of PV protease on eIF4G and NNV protease on PABPs is not reported yet. Thus, '”?'” mark is used to indicate the unfound cleavage site.

FIG 3

Displacement of PABPs by viral structure protein. In RV infected cells, viral protein NSP3 surrogate PABPs by binding to viral 3′-end tail (GACC tail instead of AAAA tail in RV mRNAs). NSP3 and RoXaN are two RV proteins that bind to eIF4G to promote viral mRNAs translation.

FIG 4

Negative regulation of PABPs by HCMV proteins. 4E-BP, a translation inhibitor binding to eIF4E, regulates cellular translation initiation. HCMV excludes 4E-BP from the translation initiation complex to promote viral mRNA translation. HCMV UL38 disassociates 4E-BP from eIF4E by enhancing its phosphorylation through the mTORC1 signal, thus relieving the inhibition of translation initiations. UL38 also increases PABPs levels in the cytoplasm, assisting viral mRNA translations. HCMV UL69 excludes 4E-BP from cap-binding complex and PABPs by indirectly interacting with eIF4A.

FIG 5

Redistribution of cytoplasmic PABPs into the infected nucleus. In herpesviruses infected cells, viral proteins such as ICP27 and UL47 in HSV-1, SOX in KSHV, and BGLF5 in EBV are required to redistribute of PABPs into the nucleus. This process inhibits cellular translation by decreasing cytoplasmic PABPs. In addition, EBV EB2 protein promotes viral mRNA export from the nucleus and associate with PABP-eIF4F to promote translation initiation of viral mRNAs.