The long and short of antiviral activity

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Science Signaling  03 Dec 2019:
Vol. 12, Issue 610, eaba3657
DOI: 10.1126/scisignal.aba3657

Only short isoforms of the pseudoenzyme PARP13 inhibit interferon responses.

Antiviral interferon signaling profoundly alters cellular gene expression and metabolism. How cells return to homeostasis after sensing type I or III interferons (IFNs) remains unclear. To identify specific RNA-binding proteins (RBPs) that may destabilize IFN transcripts, Schwerk et al. used RNA immunoprecipitation mass spectrometry. They found that the short isoform of the pseudoenzyme poly(ADP-ribose) polymerase 13 (PARP13; also known as ZAP or ZC3HAV1) bound to the 3′ untranslated region of IFNL3 mRNA but not a version with mutated AU-rich elements. In addition, the short isoform of PARP13 (PARP13-s), but not the long isoform (PARP13-l), also potentially interacted with IFNL2, IFNL3, and IFNb mRNAs. This zinc-finger antiviral protein binds multiple components of the 3′-5′ RNA decay complex and can target both viral and cellular RNAs for degradation. Indeed, loss of PARP13 increased IFNb and IFNL1/2 expression in response to RNA transfection. The authors confirmed that the expression of PARP13-s was itself stimulated by interferon, that it required alternative splicing mediated by the cleavage factor CSTF2, and that a C-terminal CAAX motif present only in PARP13-l mediated its localization to a distinct subcellular compartment from that of PARP13-s. In complementation studies, distinct isoforms exhibited opposite functions. Whereas PARP13-l had a direct antiviral role promoting degradation of Sindbis virus RNA, PARP13-s limited interferon responses and suppressed the expression of IFN-encoding mRNAs stimulated by intracellular RNA. Mutation of the CAAX motif in PARP13-l, which promoted its cytoplasmic localization, also increased its association with IFN-encoding mRNAs. Together, these data elegantly describe how the pro- or antiviral activity of an RBP may be context-dependent. Furthermore, they suggest a possible solution to the long-standing mystery of how PARP proteins with identical zinc finger domains can have unique antiviral functions.

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