Abstract
The RIG-I like receptors (RLRs) RIG-I and MDA5 are cytosolic RNA helicases best characterized as restriction factors for RNA viruses. However, evidence suggests RLRs participate in innate immune recognition of other pathogens, including DNA viruses. Kaposi’s sarcoma-associated herpesvirus (KSHV) is a human gammaherpesvirus and the etiological agent of Kaposi’s sarcoma and primary effusion lymphoma (PEL). Here, we demonstrate that RLRs restrict KSHV lytic reactivation and we demonstrate that restriction is facilitated by the recognition of host-derived RNAs. Misprocessed noncoding RNAs represent an abundant class of RIG-I substrates, and biochemical characterizations reveal that an infection-dependent reduction in the cellular triphosphatase DUSP11 results in an accumulation of select triphosphorylated noncoding RNAs, enabling their recognition by RIG-I. These findings reveal an intricate relationship between RNA processing and innate immunity, and demonstrate that an antiviral innate immune response can be elicited by the sensing of misprocessed cellular RNAs.
Highlights
The retinoic acid-inducible gene-I (RIG-I) like receptors (RLRs) RIG-I and melanoma-differentiation-associated gene 5 (MDA5) are cytosolic RNA helicases best characterized as restriction factors for RNA viruses
We first determined the contribution of each RIG-I like receptors (RLRs) sensor by depleting RIG-I, MDA5, or their adapter mitochondrial antiviral-signaling protein (MAVS), individually in the KSHVpositive cell line iSLK.219. iSLK.[219] cells contain a latent version of the Kaposi’s sarcomaassociated herpesvirus (KSHV) genome expressing a constitutive green fluorescent protein (GFP) marker, and a doxycycline (Dox)-inducible version of the major viral lytic transactivator protein, RTA, to enable entry into the lytic cycle
The viral genome contains a red fluorescent protein (RFP) marker driven by a lytic cycle-specific promoter, which can be used to monitor lytic reactivated cells. siRNA knockdown of both MDA5 and MAVS resulted in a striking increase in RFP positive cells 48 h postreactivation (Fig. 1b, c)
Summary
The RIG-I like receptors (RLRs) RIG-I and MDA5 are cytosolic RNA helicases best characterized as restriction factors for RNA viruses. We demonstrate that RLRs restrict KSHV lytic reactivation and we demonstrate that restriction is facilitated by the recognition of host-derived RNAs. Misprocessed noncoding RNAs represent an abundant class of RIG-I substrates, and biochemical characterizations reveal that an infectiondependent reduction in the cellular triphosphatase DUSP11 results in an accumulation of select triphosphorylated noncoding RNAs, enabling their recognition by RIG-I. Misprocessed noncoding RNAs represent an abundant class of RIG-I substrates, and biochemical characterizations reveal that an infectiondependent reduction in the cellular triphosphatase DUSP11 results in an accumulation of select triphosphorylated noncoding RNAs, enabling their recognition by RIG-I These findings reveal an intricate relationship between RNA processing and innate immunity, and demonstrate that an antiviral innate immune response can be elicited by the sensing of misprocessed cellular RNAs. The RIG-I-like receptor (RLR) family of PRRs is a group of cytosolic RNA helicases capable of discriminating self vs nonself RNA. The in vivo substrates that elicit RLR activation have not been identified
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