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Cell Cycle, Cell Death, and Senescence

Bad-Dependent Rafts Alteration Is a Consequence of an Early Intracellular Signal Triggered by Interleukin-4 Deprivation¹

¹ Laboratoire d'Immunologie Cellulaire et Tissulaire, Institut National de la Sante et de la Recherche Medicale U543, Hôpital Pitié Salpetrière; ² Unité de Chimie Organique, Institut Pasteur, Paris, France and ³ Equipe Hypophyse, UMR6073 INRA-Centre National de la Recherche Scientifique, Université de Tours, Physiologie de la Reproduction et des Comportements, Nouzilly, France

Requests for reprints: Angelita Rebollo, Laboratoire d'Immunologie Cellulaire et Tissulaire, Institut National de la Sante et de la Recherche Medicale U543, Hôpital Pitié Salpetrière, Bâtiment CERVI, 83, Boulevard de l'Hôpital, 75013 Paris, France. Phone: 33-142177527; Fax: 33-142177490. E-mail:rebollo{at}chups.jussieu.fr

Many molecules are inducibly localized in lipid rafts, and their alteration inhibits early activation events, supporting a critical role for these domains in signaling. Using confocal microscopy and cellular fractionation, we have shown that the pool of Bad, attached to lipid rafts in proliferating cells, is released when cells undergo apoptosis. Kinetic studies indicate that rafts alteration is a consequence of an intracellular signal triggered by interleukin-4 deprivation. Growth factor deprivation in turn induces PP1 phosphatase activation, responsible for cytoplasmic Bad dephosphorylation as well as caspase-9 and caspase-3 activation. Caspases translocate to rafts and induce their modification followed by translocation of Bad from rafts to mitochondria, which correlates with apoptosis. Taken together, our results suggest that alteration of lipid rafts is an early event in the apoptotic cascade indirectly induced by interleukin-4 deprivation via PP1 activation, dephosphorylation of cytoplasmic Bad, and caspase activation.

Key Words: Bad • Rafts • Apoptosis • Caspases • PP1 Phosphatase

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