Viral piracy of host RNA phosphatase DUSP11 by avipoxviruses

TL;DR

Avipoxviruses have borrowed a host enzyme, DUSP11, to reduce immune activation and promote infection by altering RNA metabolism.

Contribution

The discovery that avipoxviruses have co-opted a host RNA phosphatase, DUSP11, to manipulate RNA metabolism and evade immune detection.

Findings

Viral DUSP11 homologs reduce levels of endogenous RNAPIII transcripts.

Expression of vDUSP11s decreases cell sensitivity to 5’pppRNA-mediated immune activation.

vDUSP11s restore virus infection defects observed in the absence of host DUSP11.

Abstract

Proper recognition of viral pathogens is an essential part of the innate immune response. A common viral replicative intermediate and chemical signal that cells use to identify pathogens is the presence of a triphosphorylated 5’ end (5’ppp) RNA, which activates the cytosolic RNA sensor RIG-I and initiates downstream antiviral signaling. While 5’pppRNA generated by viral RNA-dependent RNA polymerases (RdRps) can be a potent activator of the immune response, endogenous RNA polymerase III (RNAPIII) transcripts can retain the 5’ppp generated during transcription and induce a RIG-I-mediated immune response. We have previously shown that host RNA triphosphatase dual-specificity phosphatase 11 (DUSP11) can act on both host and viral RNAs, altering their levels and reducing their ability to induce RIG-I activation. Our previous work explored how experimentally altered DUSP11 activity can impact immune activation, prompting further exploration into natural contexts of altered DUSP11 activity. Here, we have identified viral DUSP11 homologs (vDUSP11s) present in some avipoxviruses. Consistent with the known functions of host DUSP11, we have shown that expression of vDUSP11s: 1) reduces levels of endogenous RNAPIII transcripts, 2) reduces a cell’s sensitivity to 5’pppRNA-mediated immune activation, and 3) restores virus infection defects seen in the absence of DUSP11. Our results identify a context where DUSP11 activity has been co-opted by viruses to alter RNA metabolism and influence the outcome of infection.

Viruses face a critical challenge of disabling or avoiding host immune defenses. Cells typically recognize the presence of a virus through specific molecular markers, including triphosphorylated 5’ RNA ends that trigger immune responses. The host enzyme DUSP11 plays a key role in this process by modifying RNA and reducing immune activation. Such activity may prevent autoinflammation from host RNAs that, at least initially, start off 5’ triphosphorylated. However, so far, there are only limited contexts reported where DUSP11 activity matters during virus infection. We demonstrate here that an avipoxvirus lineage has pirated a DUSP11 gene from an ancestral host. These viral DUSP11 variants (vDUSP11s) can alter immunostimulatory host RNAs, counteract host defenses, and promote infection of a model virus. This research provides new insight into RNA biology during poxvirus infection, the overall function of viral and host DUSP11 enzymes, and more broadly how pathogens can manipulate molecular mechanisms to evade detection.

Figures