Autophagy in cell fate decisions: knowledge gained from Drosophila.

Autophagy is an important process that maintains adult tissue homeostasis and functions by protecting cells in autonomous and non-cell-autonomous ways. By degrading toxic components or proteins involved in cell signaling pathways, autophagy preserves the balance among stem cells, progenitors, and differentiated cells in various tissues. In this minireview, we discuss recent studies performed in Drosophila that highlight new roles of autophagy in adult cell fate decisions, including quiescence, proliferation, differentiation, and death.

Rab21 in enterocytes participates in intestinal epithelium maintenance.

Membrane trafficking is defined as the vesicular transport of proteins into, out of, and throughout the cell. In intestinal enterocytes, defects in endocytic/recycling pathways result in impaired function and are linked to diseases. However, how these trafficking pathways regulate intestinal tissue homeostasis is poorly understood. Using the Drosophila intestine as an in vivo system, we investigated enterocyte-specific functions for the early endosomal machinery. We focused on Rab21, which regulates specific steps in early endosomal trafficking. Depletion of Rab21 in enterocytes led to abnormalities in intestinal morphology, with deregulated cellular equilibrium associated with a gain in mitotic cells and increased cell death. Increases in apoptosis and Yorkie signaling were responsible for compensatory proliferation and tissue inflammation. Using an RNA interference screen, we identified regulators of autophagy and membrane trafficking that phenocopied Rab21 knockdown. We further showed that Rab21 knockdown-induced hyperplasia was rescued by inhibition of epidermal growth factor receptor signaling. Moreover, quantitative proteomics identified proteins affected by Rab21 depletion. Of these, we validated changes in apolipoprotein ApoLpp and the trehalose transporter Tret1-1, indicating roles for enterocyte Rab21 in lipid and carbohydrate homeostasis, respectively. Our data shed light on an important role for early endosomal trafficking, and Rab21, in enterocyte-mediated intestinal epithelium maintenance.

RAB21 interacts with TMED10 and modulates its localization and abundance.

Membrane trafficking controls vesicular transport of cargo between cellular compartments. Vesicular trafficking is essential for cellular homeostasis and dysfunctional trafficking is linked to several pathologies such as neurodegenerative diseases. Following endocytosis, early endosomes act as sorting stations of internalized materials, routing cargo toward various fates. One important class of membrane trafficking regulators are RAB GTPases. RAB21 has been associated with multiple functions and regulates integrin internalization, endosomal sorting of specific clathrin-independent cargo and autophagy. Although RAB21 is mostly associated with early endosomes, it has been shown to mediate a specific sorting event at the Golgi. From mass spectrometry data, we identified a GTP-favored interaction between RAB21 and TMED10 and 9, essential regulators of COPI and COPII vesicles. Using RAB21 knockout cells, we describe the role of RAB21 in modulating TMED10 Golgi localization. Taken together, our study suggests a new potential function of RAB21 in modulating TMED10 trafficking, with relevance to neurodegenerative disorders.