Influenza A virus nucleoprotein targets subnuclear structures

Abstract

The Influenza A virus nucleoprotein (NP) is the major protein component of the genomic viral ribonucleoprotein (vRNP) complexes, which are the replication- and transcription-competent units of Influenza viruses. Early during infection, NP mediates import of vRNPs into the host cell nucleus where viral replication and transcription take place; also newly synthesized NP molecules are targeted into the nucleus, enabling coreplicational assembly of progeny vRNPs. NP reportedly acts as regulatory factor during infection, and it is known to be involved in numerous interactions with host cell proteins. Yet, the NP-host cell interplay is still poorly understood. Here, we report that NP significantly interacts with the nuclear compartment and displays distinct affinities for different subnuclear structures. NP subnuclear behavior was studied by expression of fluorescent NP fusion proteins - including obligate monomeric NP - and site-specific fluorescence photoactivation measurements. We found that NP constructs accumulate in subnuclear domains frequently found adjacent to or overlapping with promyelocytic leukemia bodies and Cajal bodies. Targeting of NP to Cajal bodies could further be demonstrated in the context of virus infection. We hypothesize that by targeting functional nuclear organization, NP might either link viral replication to specific cellular machinery or interfere with host cell processes.

The Nucleolar Protein LYAR Facilitates Ribonucleoprotein Assembly of Influenza A Virus

“…IAV utilizes host nuclear machineries to complete various important life stages, such as transcription and replication, mRNA splicing and trafficking, and vRNP nuclear export. Previous studies have shown that there is an intense functional interplay between IAV and nucleoli ( 25 , 58 ). IAV vRNP hijacks the nucleolar proteins, such as NCL, NPM1, RRP1B, and some ribosomal proteins, to facilitate virus transcription and replication, or vRNP nuclear export ( 25 – 28 ), of which rRNA processing 1 homolog B (RRP1B) interacts with PB1 and PB2, enhancing viral transcription ( 27 ).…”

Viruses and Cajal Bodies: A Critical Cellular Target in Virus Infection?

“…Their persistence in these populations is largely due to continuous evolution of the viruses, which is driven in influenza A by the natural virus gene reservoir in aquatic birds [118]. As in other influenza viruses, influenza A has a negative-sense ssRNA genome, which is segmented into eight RNAs that exist as virus ribonucleoproteins (vRNPs) in the virus capsid [104,118,119]. Replication and transcription of the virus genome takes places in the host nucleus, by sequestering components of the nuclear machinery [120].…”

Interplay between RNA Viruses and Promyelocytic Leukemia Nuclear Bodies

“…On the other hand, PML-VI overexpression displayed antiviral effect towards PR8 (H1N1) replication but not remaining IAV strains, indicating isoform-specific antiviral effects of PML [ 82 ]. IAV matrix protein (M1), nucleoprotein (NP), and the nonstructural proteins, NS1 and NS2 (NEP) have been shown to associate with PML NBs, although the functional significance of these associations remains unclear [ 44 , 45 , 46 ].…”