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Identification of PP1 as a Caspase-9 Regulator in IL-2 Deprivation-Induced Apoptosis

Frédéric Dessauge^*, Xavier Cayla, Juan Pablo Albar, Aarne Fleischer^*, Ata Ghadiri^*, Marianne Duhamel^* and Angelita Rebollo^1,*

^* Laboratoire d’Immunologie Cellulaire et Tissulaire, Hôpital Pitié-Salpêtrière, Unité Institut National de la Santé, et de la Recherche Médicale, Paris, France; Equipe Hypophyse, Unité Mixte de Recherche 6175, Institut National de la Recherche Agronomique-Centre National de la Recherche, Université de Tours, Haras-Nationaux, Physiologie de la Reproduction et des Comportements, Nouzilly, France; and Centro Nacional de Biotecnologia, Campus de Cantoblanco, Universidad Autonoma de Madrid, Madrid, Spain

One of the mechanisms that regulate cell death is the reversible phosphorylation of proteins. ERK/MAPK phosphorylates caspase-9 at Thr¹²⁵, and this phosphorylation is crucial for caspase-9 inhibition. Until now, the phosphatase responsible for Thr¹²⁵ dephosphorylation has not been described. Here, we demonstrate that in IL-2-proliferating cells, phosphorylated serine/threonine phosphatase type 1 (PP1) associates with phosphorylated caspase-9. IL-2 deprivation induces PP1 dephosphorylation, which leads to its activation and, as a consequence, dephosphorylation and activation of caspase-9 and subsequent dissociation of both molecules. In cell-free systems supplemented with ATP caspase-9 activation is induced by addition of cytochrome c and we show that in this process PP1 is indispensable for triggering caspase-9 as well as caspase-3 cleavage and activation. Moreover, PP1 associates with caspase-9 in vitro and in vivo, suggesting that it is the phosphatase responsible for caspase-9 dephosphorylation and activation. Finally, we describe two novel phosphatase-binding sites different from the previously described PP1 consensus motifs, and we demonstrate that these novel sites mediate the interaction of PP1 with caspase-9.

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