Unraveling the dynamics of sphingolipid metabolism by mass spectrometry based (phospho)proteomics

Abstract

Sphingolipids (SLs) are essential components of cell membranes and are broad-range bioactive signaling molecules with imbalances affecting cellular function and contributing to pathologies ranging from neurodegenerative and metabolic disorders to cancer and aging. Deciphering how SL homeostasis is maintained and uncovering new regulators are key aspects for understanding lipid biology and for defining opportunities for therapeutic interventions. Protein phosphorylation might provide a rapid and reversible way of modulating the activity of SL biosynthesis. However, the exact extent and role of protein phosphorylation in SL homeostasis is, to date, unknown. Mass spectrometry (MS) based proteomics has become a valuable tool to analyze and perform temporal profiling of the phosphorylation events occurring within cells, tissues or organisms submitted to different environmental conditions. The work presented in this thesis allowed to meticulously identify phosphorylation events occurring on several crucial sphingolipid signaling pathways to better understand how misregulation of phosphoprotein signaling can be linked to sphingolipidose pathologies.