PARP12 involvement in stress response and in intracellular membrane traffic

Poly-ADP-ribose-polymerases (PARPs) and the reaction product poly-ADP-ribose (PAR) intervene in diverse cellular functions, including DNA-damage 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. Herein, we describe the behaviour of one of these PARPs -PARP12- and show that this enzyme contributes to cell response to oxidative stress, by translocating from the Golgi complex to the newly-formed stress granules, preventing in this way intracellular-membrane transport progression. PARP12 translocation to stress granules requires PARP1 activation and release of nuclear PAR that, in turn, is directly recognized by PARP12 through its 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, as a consequence, the disassembly of the Golgi membranes, followed by a block in the anterograde membrane traffic. Notably, Golgi complex organization and membrane traffic can be rescued by reverting the stress condition (by drug wash-out) as well as by inhibiting the nuclear signal. Altogether these data highlight 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.