PARP1-produced poly-ADP-ribose causes the PARP12 translocation to stress granules and impairment of Golgi complex functions

Abstract

Poly-ADP-ribose-polymerases (PARPs) 1 and 2 are nuclear enzymes that catalyze the poly-ADP-ribosylation of nuclear proteins transferring poly-ADP-ribose (PAR) polymers to specific residues. PARPs and PAR intervene in diverse functions, including DNA repair in the nucleus and stress granule assembly in the cytoplasm. Stress granules contribute to the regulation of translation by clustering and stabilizing mRNAs as well as several cytosolic PARPs and signaling proteins to modulate cell metabolism and survival. Our study is focused on one of these PARPs, PARP12, a Golgi-localized mono-ADP-ribosyltransferase that under stress challenge reversibly translocates from the Golgi complex to stress granules. PARP1 activation and release of nuclear PAR drive this translocation by direct PAR binding to the PARP12-WWE domain. Thus, PAR formation functionally links the activity of the nuclear and cytosolic PARPs during stress response, determining the release of PARP12 from the Golgi complex and the disassembly of the Golgi membranes, followed by a block in anterograde-membrane traffic. Notably, these functions can be rescued by reverting the stress condition (by drug wash-out). Altogether these data point at a novel, reversible nuclear signaling that senses stress to then act on cytosolic PARP12, which in turn converts the stress response into a reversible block in intracellular-membrane traffic.

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

“…This activity has been linked to the ZnF domains, as mutations in the ZnF domains abrogated the ability of PARP12 to move to stress granules (Welsby et al 2014). The translocation of PARP12 may also depend on PARP1 acting as a stress sensor in the nucleus, as an increase in unconjugated PAR is a key factor that promotes the recruitment of PARP12 to stress granules (Catara et al 2017). The translocation of PARP12 to stress granules is reversible, as it relocates back to the Golgi once the stress is relieved.…”

Alphavirus nsP3 ADP-ribosylhydrolase Activity Disrupts Stress Granule Formation

“…As an increasing amount of nsP3 is expressed over the course of infection, a higher level of ADP- Page 17 ribosylhydrolase activity will suppress the rate of SG assembly and thereby shift the dynamic equilibrium towards the disappearance of SG in the late stage of the replication cycle. [25,26,29]. It would be of interest to explore whether PAR plays a role in re-assortment of proteins in non-membranous structures in general.…”

“…PAR, like RNA, has been proposed to seed formation of non-membranous structures by facilitating the high concentration of low complexity region-containing proteins locally through noncovalent binding to the repetitive monomeric units of the polymer [19,[25][26][27][28]. The non-covalent PAR-protein interaction also facilitates the targeting of specific proteins to SGs [25,26,29], such as TDP-43-a key protein involved in several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Such a targeting mechanism based on PAR-binding to protein is proposed to regulate TDP-43 localization and prevent the formation of pathological aggregates in ALS patients [25,26].Certain PARP inhibitors prevent the neurotoxicity in neuronal cells [26,30], suggesting that pharmacological modulation of PAR-mediated protein targeting could have potential therapeutic benefit.…”

PARP12-catalyzed mono-ADP-ribosylation of Golgin-97 controls the transport of E-cadherin

“…So far, ADP-ribosylation has been mainly related to stress conditions, as exemplified by the role of PARP1-mediated PARylation during DNA-damage response (Luo and Kraus, 2012), or PARP5, -12 and -13 role in stress granule formation (Catara et al, 2017;Leung, 2014;Leung et al, 2011), or PARP16 in the unfolded protein response (Di Paola et al, 2012;Jwa and Chang, 2012). In oxidative stress, PARP-derived Poly-ADP-ribose (PAR) forms the backbone essential in the formation of stress granules (SGs), non-membranous structures assembled following different kind of stresses (Buchan and Parker, 2009;Kedersha and Anderson, 2002).…”