Cross-species analysis of viral nucleic acid interacting proteins identifies TAOKs as innate immune regulators

Abstract

The cell intrinsic antiviral response of multicellular organisms developed over millions of years and critically relies on the ability to sense and eliminate viral nucleic acids. Here we use an affinity proteomics approach in evolutionary distant species (human, mouse and fly) to identify proteins that are conserved in their ability to associate with diverse viral nucleic acids. This approach shows a core of orthologous proteins targeting viral genetic material and species-specific interactions. Functional characterization of the influence of 181 candidates on replication of 6 distinct viruses in human cells and flies identifies 128 nucleic acid binding proteins with an impact on virus growth. We identify the family of TAO kinases (TAOK1, −2 and −3) as dsRNA-interacting antiviral proteins and show their requirement for type-I interferon induction. Depletion of TAO kinases in mammals or flies leads to an impaired response to virus infection characterized by a reduced induction of interferon stimulated genes in mammals and impaired expression of srg1 and diedel in flies. Overall, our study shows a larger set of proteins able to mediate the interaction between viral genetic material and host factors than anticipated so far, attesting to the ancestral roots of innate immunity and to the lineage-specific pressures exerted by viruses.

Computational Mapping of the Human-SARS-CoV-2 Protein-RNA Interactome

“…We find that SECReTE-associated RBPs are predominantly found in some clusters of Figure 3c (cluster 3 and 6-8), while showing an apparent depletion in others (cluster 1-2, Figure 3c). For instance, 5 (out of 9) SECReTE-associated RBPs (SF3B4, U2AF2, GPKOW, TARDBP and NONO) are found in cluster 6, with TARDBP and NONO being functinally associated to viral regulation (85; 65). Cluster 3 contains 5 (out of 12) SECReTE-associated RBPs, namely CSTF2, ELAVL4, HNRNPC, PTBP1 and QKI, each associated with multiple RNA functional processes, including RNA stability, 3’-end formation, splicing and translation (85).…”

“…Cluster 1 predominantly harbors RBPs with binding preference for the viral 3’ UTR, including regulators of RNA stability and proteins involved in 3’ end formation and/or regulation of translation. Among those RBPs, the poly (I:C) binding protein KHDRBS1 has been identified to have pro-viral activity in SFV infection (65), while the multifunctional RBP PCBP1, along with hnRNPRs has been shown to be implicated in translational control of many viruses, including poliovirus, human pailloma virus and Hepatitis A virus. Cluster 6 is comprised of RBPs which preferentially bind to the 5’ UTR of SARS-CoV-2.…”

“…Previous studies have suggested that ELAVL human proteins might be affected during infections by the viral RNA that acts as a competitor to tritate them away from their cellular mRNA targets (66). While most RBPs in cluster 8 were not found to be functionally related in literature, RBPs KHSRP and MATR3 have been shown to act as restriction factors in SINV infection (65)…”

“…Previous studies have suggested that ELAVL human proteins might be affected during infections by the viral RNA that acts as a competitor to tritate them away from their cellular mRNA targets (66). While most RBPs in cluster 8 were not found to be functionally related in literature, RBPs KHSRP and MATR3 have been shown to act as restriction factors in SINV infection (65) Predicted RBP binding sites overlap with SECReTE motifs Haimovich et al (27) recently identified the presence of a unique cis-acting RNA element, termed "SECReTE" motif, which consists of 10 or more consecutive triplet repeats, with a C or a U present at every third base, on the sequences of both (-) and (+)ssRNA viruses. In context of SARS-CoV-2, a total of 40 SECReTE motifs have been identified in the viral genome, with a total length of ~1.3 kilobase.…”

Comprehensive Analysis of Innate Immunophenotyping Based on Immune Score Predicting Immune Alterations and Prognosis in Breast Cancer Patients

“…Recently, the new upsurge of tumor research from tumor immunity and tumor microenvironment were stimulated, and it is believed that tumor immunity will be the most powerful weapon to overcome cancer treatment [ 9 , 10 , 11 ]. With the progress of cancer immunotherapy, the importance of innate immune systems in antitumor were gradually attracted the attention of researchers [ 12 , 13 , 14 , 15 , 16 ]. Innate immune response as the first line and connect to adaptive immunity for protect the human body stay away from pathogens and tumors through multi-type special immune cells and pathways.…”