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Raft component GD3 associates with tubulin following CD95/Fas ligation

Maurizio Sorice^*,, Paola Matarrese, Antonella Tinari, Anna Maria Giammarioli, Tina Garofalo^*,, Valeria Manganelli^*, Laura Ciarlo, Lucrezia Gambardella, Giorgio Maccari^||, Maurizio Botta^||, Roberta Misasi^* and Walter Malorni^,1

^* Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy;

Laboratory of Experimental Medicine and Environmental Pathology, Sapienza University, Rieti, Italy;

Section of Cell Aging and Degeneration, Department of Drug Research and Evaluation, and

Section of Ultrastructural Infectious Pathology, Department of Technology and Health, Istituto Superiore di Sanità, Rome, Italy; and

^|| Department of Chemical Technology of Drugs, University of Siena, Siena, Italy

¹ Correspondence: Department of Drug Research and Evaluation, Section of Cell Aging and Degeneration, Istituto Superiore di Sanità, viale Regina Elena 299, 00161, Rome, Italy. E-mail: malorni{at}iss.it

In a previous investigation, we demonstrated that after CD95/Fas triggering, raft-associated GD3 ganglioside, normally localized at the plasma membrane of T cells, can be detected in mitochondria, where they contribute to apoptogenic events. Here, we show the association of the glycosphingolipid GD3 with microtubular cytoskeleton at very early time points following Fas ligation. This was assessed by different methodological approaches, including fluorescence resonance energy transfer, immunoelectron microscopy, and coimmunoprecipitation. Furthermore, docking analysis also showed that GD3 has a high affinity for the pore formed by 4 tubulin heterodimers (type I pore), thus suggesting a possible direct interaction between tubulin and GD3. Finally, time-course analyses indicated that the relocalization of GD3 to the mitochondria was time related with the alterations of the mitochondrial membrane potential. Hence, microtubules could act as tracks for ganglioside redistribution following apoptotic stimulation, possibly contributing to the mitochondrial alterations leading to cell death.—Sorice, M., Matarrese, P., Tinari, A., Giammarioli, A. M., Garofalo, T., Manganelli, V., Ciarlo, L., Gambardella, L., Maccari, G., Botta, M., Misasi, R., Malorni, W. Raft component GD3 associates with tubulin following CD95/Fas ligation.

Key Words: apoptosis • mitochondria • ganglioside • cytoskeleton