PARP13 regulates cellular mRNA post-transcriptionally and functions as a pro-apoptotic factor by destabilizing TRAILR4 transcript

Abstract

Poly(ADP-ribose) polymerase-13 (​PARP13/​ZAP/​ZC3HAV1) is an antiviral factor, active against specific RNA viruses such as murine leukaemia virus, Sindbis virus and human immunodeficiency virus. During infection, ​PARP13 binds viral RNA via its four CCCH-type zinc-finger domains and targets it for degradation by recruiting cellular messenger RNA (mRNA) decay factors such as the exosome complex and ​XRN1. Here we show that ​PARP13 binds to and regulates cellular mRNAs in the absence of viral infection. Knockdown of ​PARP13 results in the misregulation of hundreds of transcripts. Among the most upregulated transcripts is ​TRAILR4 that encodes a decoy receptor for ​TRAIL—a pro-apoptotic cytokine that is a promising target for the therapeutic inhibition of cancers. ​PARP13 destabilizes ​TRAILR4 mRNA post-transcriptionally in an exosome-dependent manner by binding to a region in its 3′ untranslated region. As a consequence, ​PARP13 represses ​TRAILR4 expression and increases cell sensitivity to ​TRAIL-mediated apoptosis, acting as a key regulator of the cellular response to ​TRAIL.