EPG5 is a metazoan-specific autophagy protein that is also essential for endocytic recycling and endocytic degradation, due to being a Rab7 effector. Mutations in EPG5 have been linked to Vici syndrome, a multi-system disorder that is characterised by, for instance, myopathy and combined immunodeficiency, with affected cells showing an accumulation of non-degradative autolysosomes. However, the molecular mechanisms that underlie the observed phenotypes remain unclear. In their study (Wang et al., 2019), Hong Zhang and colleagues performed a screen in C. elegans for genes that suppress the autophagy defect in epg-5 mutants. They demonstrate that loss of rbg-1 and rbg-2 alleviates this effect by promoting lysosomal activity. RBG-1 and RBG-2 form a complex that acts as a GAP for RAB3 and a GEF for RAB18; however, the effect of the complex in overcoming the loss of epg-5 is independent of this activity. Instead, the authors show here that loss of rbg-1 rescues the reduced motility of lysosome-associated RAB7 observed upon epg-5 mutation, suggesting that RBG-1 modulates RAB7 dynamics. Indeed, expression of an inactive GDP-bound form of RAB7 has the same effects as loss of rbg-1, providing further support for a role of RBG-1 in regulating RAB7 to modulate lysosome biogenesis and thus autophagy. This work, therefore, not only describes a new role for the RBG-1–RBG-2 complex in regulating RAB7 cycling, but also provides new molecular insights into the pathogenesis of Vici syndrome.
Role of RBG-1 and RBG-2 in modulating lysosome biogenesis
Role of RBG-1 and RBG-2 in modulating lysosome biogenesis. J Cell Sci 1 October 2019; 132 (19): e1901. doi:
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