RAB24, novel insights about its role in autophagy.

GERM, EMILIANO; AMAYA, CELINA; ABBA, ROMINA; COLOMBO M.I.

Congreso; SAIB - SAMIGE Joint meeting 2021 on line.; 2021

SAIB (Sociedad Argentina de Investigación en Bioquímica y Biología Molecular)

Autophagy is a highly-conserved intracellular pathway that delivers cytoplasmic components to the lysosomes, such as molecules and organelles, in order to preserve cellular homeostasis. The process is characterized by the formation of double membrane vesicles called autophagosomes, which internalize and transport the material to the lysosomes for subsequent degradation. Autophagic dysregulation is implicated in various diseases, including neurodegeneration, cancer and infections; therefore, the pathway must be finely controlled. mTORC1 is a serine/threonine protein kinase, considered a master regulator of energy metabolism and cell growth. This kinase acts as a major suppressor of autophagy, integrating both intracellular and extracellular signals to control the autophagic process in a synchronized fashion. The Rab proteins constitute the most numerous families of small GTPases, which guide intracellular vesicular traffic events, including autophagy. Previously, our group has demonstrated that Rab24 participates in the endosome degradation process and autophagy, but little is known about its precise role in this latter pathway. Indeed, lysosomes and late endosomes are essential in mTORC1 signaling. An intimate relationship between mTORC1 activity and lysosomal association, and its role in autophagy control has been demonstrated. We have studied, in different cellular models, the role of Rab24 and its possible interplay with mTORC1, using several techniques, such as protein transfection, RNAi knockdown, immunofluorescence and Western blot assays. Our results indicate that Rab24 depletion, or overexpression of a dominant negative mutant seems to modify mTORC1 association with lysosomal compartments. In addition, the processing of the autophagic protein LC3 is also affected, altering the initial steps of autophagy. Our present results locate Rab24 as a novel positive regulator of autophagosome formation and reveal significant insights about the role of this Rab protein in this process.