S-palmitoylation: a new layer of regulation for Akt

ANALÍA AMANTE; ANTONELLA VILA; MARÍA CORVI; ALEJANDRO COLMAN-LERNER; MATÍAS BLAUSTEIN

Congreso; Reunión Anual de la Sociedad Argentina de Investigación Bioquímica y Biología Molecular; 2022

Akt/PKB protein kinase is involved in a wide variety of physiological processes, including cell metabolism, proliferation, and survival, as well as pathological processes such as viral infection andmalignant transformation. Thus, it is not surprising that different clinical trials are underway to test the efficacy of a variety of inhibitors of the Akt pathway as anticancer and antiviral treatments.In recent years, new Akt post-translational modifications (PTMs) have been found, which have been reported to affect its activity. However, it is not fully understood how these modificationpatterns affect certain key features of Akt such as its target specificity, localization, and function. Our hypothesis is that the molecular code of Akt, that is, the profile of Akt PTMs, can determine itssubcellular localization and vice versa, regulating Akt function.In the present work, we experimentally demonstrate that Akt can undergo S- palmitoylation, a PTM related to protein sorting through subcellular membranes, which has been shown to affectseveral oncogenic proteins. Using a strategy that combines the use of palmitoylation-deficient Akt mutants, palmitoylation inhibitors and fluorescence imaging of human cell lines, we show that thisPTM affects Akt localization as well as its activation. On the other hand, by using an in vitro adipocyte cell model, we demonstrate that S-palmitoylation is involved in the differentiation of thesecells. Finally, by using flow cytometric techniques, we show that blockade of S-palmitoylation affects essential cellular processes such as death and survival in different human cell lines.Understanding the relationship between the molecular code and the cell´s decision-making brings us closer to understanding how these PTMs influence the development and progression ofdiseases such as cancer. In particular, our data support a role for Akt S palmitoylation in the phosphorylation, localization, and function of this kinase, influencing key processes such as celldifferentiation and death.