Rab GTPases are evolutionarily conserved signals mediating selective autophagy.

Abstract

Selective autophagy plays a crucial role in maintaining cellular homeostasis by specifically targeting unwanted cargo labeled with "autophagy cues" signals for autophagic degradation. In this study, we identify Rab GTPases as a class of such autophagy cues signals involved in selective autophagy. Through biochemical and imaging screens, we reveal that human Rab GTPases are common autophagy substrates. Importantly, we confirm the conservation of Rab GTPase autophagic degradation in different model organisms. Rab GTPases translocate to damaged mitochondria, lipid droplets, and invading Salmonella-containing vacuoles (SCVs) to serve as degradation signals. Furthermore, they facilitate mitophagy, lipophagy, and xenophagy, respectively, by recruiting receptors. This interplay between Rab GTPases and receptors may ensure the de novo synthesis of isolation membranes around Rab-GTPase-labeled cargo, thereby mediating selective autophagy. These processes are further influenced by upstream regulators such as LRRK2, GDIs, and RabGGTase. In conclusion, this study unveils a conserved mechanism involving Rab GTPases as autophagy cues signals and proposes a model for the spatiotemporal control of selective autophagy.