Critical Nodes of Virus–Host Interaction Revealed Through an Integrated Network Analysis

Korbinian Bösl; Aleksandr Ianevski; Thoa T. Than; Petter I. Andersen; Suvi Kuivanen; Mona Teppor; Eva Zusinaite; Uga Dumpis; Astra Vitkauskiene; Rebecca J. Cox; Hannimari Kallio-Kokko; Anders Bergqvist; Tanel Tenson; Valentyn Oksenych; Magnar Bjørås; Marit W. Anthonsen; David Shum; Mari Kaarbø; Olli Vapalahti; Marc P. Windisch; Giulio Superti-Furga; Berend Snijder; Denis Kainov; Richard K. Kandasamy

Proteins usually fold into stable three-dimensional structures that mediate specific functions. In addition, there are sub-structures in proteins termed "intrinsically disordered regions (IDRs)" which lack stable structures under normal physiological conditions. IDRs are required for multiple cellular functions even though they lack these defined structures (Oldfield and Dunker 2014) . Many studies have highlighted the presence of such IDRs in viral proteins (Xue et al. 2014 , Tamarozzi and Giuliatti 2018 , Dyson and Wright 2018 , such as E6 from human papilloma virus, that are crucial for hijacking the cellular machinery. We analysed the host proteins from the hvPPI for presence of IDRs using the prediction software IUPred (Meszaros et al. 2018 ). We found a statistically significant enrichment (p-value < 6.246 × 10 −06 ) of IDRs in the host proteins targeted by viruses ( Fig. 2A and Fig. S2A ). We then identified the subnetwork in the hvPPI which contained the top host targets with high disorderness score (Fig. 2B) . The top five proteins with large IDRs include CD44 antigen (CD44), Serine/arginine repetitive matrix protein 2 (SRRM2), Myristoylated alanine-rich C-kinase substrate (MARCKS), BAG family molecular chaperone regulator 3 (BAG3) and Mitochondrial antiviral-signalling protein (MAVS) (Fig. 2C ). CD44 is a marker of exhausted CD8+ T cells (Wherry and Kurachi 2015) and replication of HCV in T cells was shown to decrease cell proliferation by inhibiting CD44 expression and signalling (Kondo et al. 2009 ). SRRM2 is a serine/arginine-rich protein involved in RNA splicing (Blencowe et al. 2000) . SRRM2 is differentially phosphorylated in HIV-1 infected cells and absence of SRRM2 lead to increased HIV-1 gene expression, since it regulates the splicing of HIV-1 (Wojcechowskyj et al. 2013 ). In the hvPPI, SRRM2 is targeted by multiple viral proteins including the Tat protein from HIV-1. Tat protein has an important role in the stimulation of the transcription of the long terminal repeat (LTR) (Das et al. 2011 ). In addition, NS1 protein from influenza B virus has also been reported to interact with SRRM2 (Patzina et al. 2017) . Proteins of the MARCKS family are involved in a range of cellular processes including cell adhesion and migration (Arbuzova et al. 2002) . MARCKS is a negative regulator of lipopolysaccharide (LPS)-induced Toll-like receptor 4 (TLR4) signalling in mouse macrophages (Mancek-Keber et al. 2012) . MAVS is an adaptor protein in the RIG-I signalling pathway involved in the sensing of RNA. Ablasser et al. (2009) reported that double-stranded DNA serves as a template for RNA polymerase II and is transcribed into a 5' triphosphate containing double-stranded RNA, which activates the RIG-I signalling pathway. In the hvPPI, MAVS is targeted by several proteins from dsDNA viruses such as EBV and HPV. Altogether, our analysis shows that the IDR-high part of the human proteome is an essential part of the viral evasion strategy and some of the selected targets highlighted here could show novel insights into the viral evasion mechanisms. However, the very flexible protein structure of disordered proteins also makes them also difficult to target with drugs. preprint author/funder. All rights reserved. No reuse allowed without permission.