Comparative influenza protein interactomes identify the role of plakophilin 2 in virus restriction

Abstract

Cellular protein interaction networks are integral to host defence and immune signalling pathways, which are often hijacked by viruses via protein interactions. However, the comparative virus–host protein interaction networks and how these networks control host immunity and viral infection remain to be elucidated. Here, we mapped protein interactomes between human host and several influenza A viruses (IAV). Comparative analyses of the interactomes identified common and unique interaction patterns regulating innate immunity and viral infection. Functional screening of the ‘core‘ interactome consisting of common interactions identified five novel host factors regulating viral infection. Plakophilin 2 (PKP2), an influenza PB1-interacting protein, restricts IAV replication and competes with PB2 for PB1 binding. The binding competition leads to perturbation of the IAV polymerase complex, thereby limiting polymerase activity and subsequent viral replication. Taken together, comparative analyses of the influenza–host protein interactomes identified PKP2 as a natural inhibitor of IAV polymerase complex.

The dynamic proteome of influenza A virus infection identifies M segment splicing as a host range determinant

“…However, it is critical to also emphasize that this is not the only relevant factor for IAV host range. For example, despite the overall similar host response, we and others have previously described host factors affecting human and avian virus infections [20][21][22][23]25,32 . It is also well-established that the RdRp of avian-adapted strains is less active in human cells 8,9 .…”

“…For example, RNAi screens identified host factors required for IAV replication [21][22][23] . Also, interaction proteomics experiments identified many cellular binding partners of IAV proteins [24][25][26] . A number of studies also quantified changes in protein abundance [27][28][29][30][31][32] .…”

Response Modifiers: Tweaking the Immune Response Against Influenza A Virus

“…Several genetic and proteomic screens have identified several promising hits with potential roles in the IV replication cycle (80)(81)(82)(83)(84)(85)(86)(87)(88)(89)(90). In addition to these genome-wide screens, viral and host protein interactions can be mapped into networks that can also be used to identify host factors critical for IV replication (91,92). Interestingly, meta-analysis of some these studies shows limited overlap in the genes/proteins identified as required host factors (87,(93)(94)(95).…”

Beyond Channel Activity: Protein-Protein Interactions Involving Viroporins

“…More suitable methods detect interactions in the context of the infected cell, using a combination of affinity purification with mass spectrometry, e.g., Wang et al (2017), although the method has also low sensitivity. Other methods are based on microarrays of deposited purified proteins (Zhu et al 2001) and protein complementation assay (PCA) (Tarassov et al 2008).…”

“…This study also detected nine interactions between IAV M2 and host proteins, among them RNA-binding proteins, transcription factors, or proteins involved in signaling pathways, or to detect intraviral PPIs; (b) close-up of high-confidence candidate-interacting proteins (HCIPs) associated with multiple IAV strains when M2 was used as bait. Indicated are links to other viral proteins (NP, PB1, and PB2) [adapted from Wang et al (2017)] HCV encodes a single polyprotein of ~3000 amino acids that is cleaved by cellular and viral proteases into ten different proteins: three structural proteins (core, E1, and E2) and seven nonstructural proteins (p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B). The structural proteins Core (C), E1, and E2 are located in the N-terminal region and form the viral particle (Moradpour and Penin 2013), whereas NS3 to NS5B are involved in the replication of the viral genome.…”