Akt Is S-Palmitoylated: A New Layer of Regulation for Akt.
Blaustein, M., Piegari, E., Martinez Calejman, C., Vila, A., Amante, A., Manese, M. V., Zeida, A., Abrami, L., Veggetti, M., Guertin, D. A., van der Goot, F. G., Corvi, M. M. and Colman-Lerner, A.
Departamento de Fisiologia, Biologia Molecular y Celular (DFBMC), Facultad de Ciencias Exactas y Naturales (FCEN), Universidad de Buenos Aires (UBA), Buenos Aires, Argentina.
Instituto de Fisiologia, Biologia Molecular y Neurociencias (IFIBYNE), Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET)-UBA, Buenos Aires, Argentina.
Instituto de Biociencias, Biotecnologia y Biologia Traslacional (iB3), Universidad de Buenos Aires, Buenos Aires, Argentina.
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, United States.
Laboratorio de bioquimica y biologia celular de parasitos, Instituto Tecnologico de Chascomus (IIB-INTECH), Universidad Nacional de San Martin (UNSAM) - CONICET, Chascomus, Argentina.
Departamento de Bioquimica and Centro de Investigaciones Biomedicas (CEINBIO), Facultad de Medicina, Universidad de la Republica, Montevideo, Uruguay.
Global Health Institute, Ecole Polytechnique Federale de Lausanne (EPFL), Lausanne, Switzerland.
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, United States.
Lei Weibo Institute for Rare Diseases, University of Massachusetts Medical School, Worcester, MA, United States.
The protein kinase Akt/PKB participates in a great variety of processes, including translation, cell proliferation and survival, as well as malignant transformation and viral infection. In the last few years, novel Akt posttranslational modifications have been found. However, how these modification patterns affect Akt subcellular localization, target specificity and, in general, function is not thoroughly understood. Here, we postulate and experimentally demonstrate by acyl-biotin exchange (ABE) assay and (3)H-palmitate metabolic labeling that Akt is S-palmitoylated, a modification related to protein sorting throughout subcellular membranes. Mutating cysteine 344 into serine blocked Akt S-palmitoylation and diminished its phosphorylation at two key sites, T308 and T450. Particularly, we show that palmitoylation-deficient Akt increases its recruitment to cytoplasmic structures that colocalize with lysosomes, a process stimulated during autophagy. Finally, we found that cysteine 344 in Akt1 is important for proper its function, since Akt1-C344S was unable to support adipocyte cell differentiation in vitro. These results add an unexpected new layer to the already complex Akt molecular code, improving our understanding of cell decision-making mechanisms such as cell survival, differentiation and death.
Front Cell Dev Biol 9: 626404 (2021)