From the Golgi complex to the stress granules: the multiple functions of PARP12

The cellular events regulated by mono-ADPribosyltransfeases (mARTs) have been recently reviewed and include functions as diverse as immune response, transcriptional control, cell survival and stress responses (1, 2). When cells are exposed to a variety of stress stimuli, they respond with the activation of stress-related pathways including the formation of stress granules (SGs), considered to be dynamic triage centers that sort mRNA for storage, decay, or re-initiation under stress conditions (3). It has been reported that cytoplasmic SG assembly and maintenance is mediated by poly ADP-ribose (pADPr), while specific polyADP-ribosyl-polymerases (PARPs) and polyADP-ribosyl glycohydrolases (PARG) localise at these structures regulating mRNAs translation in response to stress (4). The molecular basis of these processes remain to be clarified. Among the SG-PARPs, we investigated the role played by PARP12 in HeLa cells under oxidative stress. Here we show that under physiological conditions PARP12 is localised at the Golgi complex. In response to different stress stimuli endogenous PARP12 translocate from the Golgi complex to SGs; as soon as the stress is relieved, this enzyme translocate back to the Golgi complex. To understand the molecular mechanisms responsible for such shuttling, a functional analysis of the protein domains has been undertaken. Our data reveal that while the catalytic domain is dispensable for PARP12 localisation at SGs, both the zinc finger and the WWE domains are required. Since the WWE domain has been reported to constitute a PAR-binding module (5), the role of both PARP12-WWE domains and PAR has been investigated with reference to the mechanism of stress response. 1.Vyas S. et al., Family-wide analysis of poly(ADP-ribose) polymerase activity. Nat Commun.2014,Jul 21;5:4426 2.Grimaldi G. et al., From toxins to mammalian enzymes: the diversity of mono-ADP-ribosylation. Front Biosci (Landmark Ed).2015, Jan 1;20:389-404 3.Buchan J. R. and Parker R. Eukaryotic stress granules: the ins and outs of translation. Mol Cell, 2009, 36(6), 932-41 4.Leung AK. et al., Poly(ADP-ribose) regulates stress responses and microRNA activity in the cytoplasm. Mol Cell. 2011, May 20;42(4):489-99 5.Andrabi S. et al., Iduna protects the brain from glutamate excitotoxicity and stroke by interfering with poly(ADP-ribose) polymer-induced cell death. Nature Medicine 2011, 17, 692-699.