Mitochondrial damage elicits a TCDD-inducible poly(ADP-ribose) polymerase-mediated antiviral response

Abstract

The innate immune system senses RNA viruses by pattern recognition receptors (PRRs) and protects the host from virus infection. PRRs mediate the production of immune modulatory factors and direct the elimination of RNA viruses. Here, we show a unique PRR that mediates antiviral response. Tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly(ADP ribose) polymerase (TIPARP), a Cysteine3 Histidine (CCCH)-type zinc finger-containing protein, binds to Sindbis virus (SINV) RNA via its zinc finger domain and recruits an exosome to induce viral RNA degradation. TIPARP typically localizes in the nucleus, but it accumulates in the cytoplasm after SINV infection, allowing targeting of cytoplasmic SINV RNA. Redistribution of TIPARP is induced by reactive oxygen species (ROS)-dependent oxidization of the nuclear pore that affects cytoplasmic-nuclear transport. BCL2-associated X protein (BAX) and BCL2 antagonist/killer 1 (BAK1), B-cell leukemia/lymphoma 2 (BCL2) family members, mediate mitochondrial damage to generate ROS after SINV infection. Thus, TIPARP is a viral RNA-sensing PRR that mediates antiviral responses triggered by BAX-and BAK1-dependent mitochondrial damage.innate immunity | antiviral response | mitochondrial damage | RNA degradation | reactive oxygen species

The impact of PARPs and ADP-ribosylation on inflammation and host–pathogen interactions

“…Like PARP12, TiPARP was also shown to block VEEV replication and inhibit cellular translation when transduced into cells by a VEEV replicon (Atasheva et al 2014). In a separate study, siRNA knockdown of TiPARP in U373 human astrocyte cells led to increased replication of SINV and rubella virus replication (Kozaki et al 2017). The increase in SINV replication was also demonstrated in TiParp −/− mice.…”

“…PARP7 (TiPARP) PARP7, also known as tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly-ADP-ribose polymerase (TiPARP), has a single ZnF domain that mediates RNA binding. It also has a WWE domain and a PARP catalytic domain capable of mono-ADP-ribosylation (Kozaki et al 2017).…”

The coronavirus macrodomain is required to prevent PARP-mediated inhibition of virus replication and enhancement of IFN expression

“…Notably, the expression of PARP7 and PARP13 following infection were upregulated in infected IFNAR -/-BMDMs (Fig 3B), suggesting that they are part of an IFN-independent cellular response to infection. In addition, knockdown of either PARP7 or PARP10 mRNA mildly reduced gRNA production in cells infected with either WT or N1347A virus (Fig 5A), suggesting that they have pro-viral functions in MHV-infected BMDMs, perhaps analogous to alphavirus-infected cells but in contrast to other virus infection models where they are known to be antiviral [30,38].…”

“…In other cases, ADP-ribosylation is important for efficient virus replication as PARP1 inhibitors restrict the replication of several viruses such as herpesviruses, adenoviruses, and HIV [35][36][37]. PARP7 has both anti-and pro-viral activities as it binds to and induces degradation of Sindbis virus RNA [30,38] but also promotes influenza A virus infection by ADP-ribosylating TBK1, which inhibits type I IFN (IFN-I) production [39]. Finally, sirtuins 1-7, including the ADP-ribosylating sirtuins SIRT4 and SIRT6, were shown to inhibit the replication of a wide variety of DNA and RNA viruses in MRC-5 cells [18].…”

Methods to Study TCDD-Inducible Poly-ADP-Ribose Polymerase (TIPARP) Mono-ADP-Ribosyltransferase Activity

“…We therefore generated a hepatocyte-specific TIPARP deletion (Tiparp fl/fl Cre Alb ) mouse strain. We also generated a whole-body knockout TIPARP (Tiparp Ex3-/-) strain in which Tiparp is deleted by the removal of exon 3, making it distinct from other TIPARP null lines (Ahmed, et al, 2015;Kozaki et al, 2017;Schmahl, et al, 2007). Here we show that Tiparp Ex3-/and Tiparp fl/fl Cre Alb mice are both more sensitive than WT mice to dioxin-induced hepatotoxicity and lethality.…”