FIGURE 8:

Retrograde trafficking by Snx4 family proteins maintains lipid homeostasis of the vacuole membrane. The endosomal maturation pathway and autophagosome–vacuole fusion are depicted. The relative abundances and topology of PS and PE in organelle membranes are depicted. (A) We propose that during endosome maturation, the ratio of PE to PS on the membrane increases as a result of Snx4-mediated export of membrane enriched in PS (compared with retromer) and the activity of Psd2, which converts PS to PE on the endosome (Gulshan et al., 2010). This results in a PE/PS ratio on the vacuole membrane that is permissive for SNARE-mediated fusion of autophagosomes (AV) with the vacuole. Also depicted are the Snx4 family- and retromer-dependent retrograde pathways that originate from a common endosome (Ma et al., 2017). (B) In snx4Δpsd1Δ cells, the amount of PE in the cell is substantially (∼60%) reduced (Trotter et al., 1993) and PS is not adequately removed from the endosomal system, resulting in a decreased PE/PS ratio on the vacuole membrane. This manifests as a decrease in fusion competence of the vacuole, resulting in impaired fusion of autophagosomes with the vacuole and also homotypic vacuole fusion. Furthermore, it is likely that the membranes that supply biogenesis of autophagosomes also have a fusion-deficient ratio of PE/PS, resulting in an accumulation of autophagy intermediates.