SNAREs in the maturation and function of LROs

Abstract

The early/recycling endosomes of an eukaryotic cell perform diverse cellular functions. In addition, the endosomal system generates multiple organelles, including certain cell type-specific organelles called lysosome-related organelles (LROs). The biosynthesis of these organelles possibly occurs through a sequential maturation process in which the cargo-containing endosomal vesicular/tubular structures are fused with the maturing organelle. The molecular machinery that regulates the cargo delivery or the membrane fusion during LRO biogenesis is poorly understood. Here, we describe the known key molecules, such as SNAREs, that regulate both the biogenesis and secretion of multiple LROs. Moreover, we also describe other regulatory molecules, such as Rab GTPases and their effectors that modulate the SNARE activity for cargo delivery to one such LRO, the melanosome. Overall, this review will increase our current understanding of LRO biogenesis and function.

Keywords: AP-3; BLOC-1; HPS; LRO; SNARE; melanosome.

Figure 1.

Melanosome biogenesis is a typical model for studying LRO biogenesis. The biogenesis of melanosomes begins in early endosomes (Stage I) where the amyloidogenic fibrillar protein PMEL is internalized and forms fibrils (Stage II, not shown). Further, the melanin-synthesising proteins TYRP1 (BLOC-1-dependent cargo, orange symbols) and TYR (AP-3-dependent cargo, blue symbols) were delivered from tubular-vesicular structures of recycling endosomes to maturing Stage II (not shown) or Stage III melanosomes. Upon cargo transport and melanin synthesis, Stage III melanosomes mature into Stage IV melanosomes. The cargo transport to maturing melanosomes is possibly mediated by the pairing of cytosolic SNARE domains of STX13 (Qa SNARE, green) and 2 other unknown SNAREs (Qb, Qc; black) on recycling endosomes with the SNARE domain of VAMP7 (R-SNARE, black) on Stage III or Stage II (not shown) melanosomes. Moreover, the current studies suggest that BLOC-2, Rab9A, BLOC-3, Rab38/32 and VARP molecules modulate the STX13-mediated cargo delivery to melanosomes, possibly functioning during membrane fusion. In contrast, BLOC-1 and AP-3 possibly function at early steps of cargo transport or sorting, respectively. Curved arrows represent the SNARE-mediated fusion of endosomal transport carriers with melanosomes. The dotted black arrow indicates the possible route of melanosome secretion, and the dotted gray arrows represent the different routes of the endocytic pathway. The solid black lines in the Stage III melanosome represent the PMEL fibrils. The question marks indicate the roles of those molecules that need to be validated in future studies. EE, early endosome and PM, plasma membrane.