PARP13 regulates cellular mRNA post-transcriptionally and functions as a pro-apoptotic factor by destabilizing TRAILR4 transcript.
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.
1] Department of Biology, Massachusetts Institute of Technology, 500 Main Street, Cambridge, Massachusetts 02139, USA [2] Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, Massachusetts 02139, USA.
Tanya
T
Todorova
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, Massachusetts 02139, USA.
Florian J
FJ
Bock
1] Department of Biology, Massachusetts Institute of Technology, 500 Main Street, Cambridge, Massachusetts 02139, USA [2] Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, Massachusetts 02139, USA.
Paul
P
Chang
D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D055354:Exosomes / Q000235:genetics / Q000502:physiology; D055786:Gene Knockout Techniques; D006367:HeLa Cells; D006801:Humans; D012323:RNA Processing, Post-Transcriptional / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000502:physiology*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic / Q000235:genetics / Q000502:physiology*; D059467:Transcriptome / Q000235:genetics / Q000502:physiology; D053319:Tumor Necrosis Factor Decoy Receptors / Q000235:genetics / Q000502:physiology*; D016335:Zinc Fingers / Q000235:genetics / Q000502:physiology
D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C451501:TNFRSF10D protein, human; D053319:Tumor Necrosis Factor Decoy Receptors; C527496:ZC3HAV1 protein, human