IFN is recognized as an antiviral cytokine that uses STAT-family transcription factors to induce a few hundred IFN-stimulated genes (ISGs), many of which have been shown to be antiviral [
1,
2]. Several RNA viruses of the
Paramyxoviridae family, however, exhibit IFN resistance [
3,
4]. We have been following this property in selected members of this family [
5‐
9], focusing on the
Pneumovirus genus, which is comprised of two members that are severe respiratory pathogens, namely RSV, a human virus, and PVM, a mouse virus [
10,
11]. A natural mouse pathogen, PVM is lethal in laboratory mice, producing symptoms that are very similar to those of RSV disease in susceptible human subjects, whereas RSV itself replicates relatively poorly in mice, without significant mortality [
10‐
12]. Thus, PVM infection in mice has often been recommended as an alternative model for human RSV infection [
12]. Regarding innate immunity of the host, both viruses code for two nonstructural proteins, NS1 and NS2, that suppress IFN, which is essential for robust growth of the virus and the resultant pathology [
13‐
23]. However, despite intensive research, the exact molecular mechanism of this important function of NS proteins remains unknown [
6‐
8,
24‐
27]. Intriguingly, the primary structures of the NS proteins show no similarity with any other protein in biology; thus, bioinformatic analysis of their sequences offers no clue to their evolutionary origin or functional domains [
6,
9,
24]. Except for the recently solved crystal structure of RSV NS1 [
28], the higher order structure of the pneumoviral NS proteins has also remained unknown, in part due to difficulties of expression of the recombinant proteins; moreover, the crystal structure of RSV NS1 [
28] did not offer any mechanistic insight into its IFN-suppressive function. Nonetheless, we have recently shown that the PVM NS proteins specifically degrade several mouse ISGs, namely IFITM1, TRAFD1 and ISG20 [
24]. At this point, we argued that a comparison between the NS proteins of the two pneumoviruses may shed light on their structure and function. Thus, we proceeded to test if the RSV NS proteins target any ISGs, and if so, whether they are same or different from those targeted by their PVM counterparts.