Abstract
Rab7 – or in yeast, Ypt7p – governs membrane trafficking in the late endocytic and autophagic pathways. Rab7 also regulates mitochondrion-lysosome contacts, the sites of mitochondrial fission. Like all Rab GTPases, Rab7 cycles between an “active” GTP-bound form that binds downstream effectors – e.g., the HOPS and retromer complexes and the dynactin-binding Rab-interacting lysosomal protein (RILP) – and an “inactive” GDP-bound form that cannot bind effectors. Accessory proteins regulate the nucleotide binding state of Rab7: guanine nucleotide exchange factors (GEFs) stimulate exchange of bound GDP for GTP, resulting in Rab7 activation, whereas GTPase activating proteins (GAPs) boost Rab7’s GTP hydrolysis activity, thereby inactivating Rab7. This review will discuss the GEF and GAPs that control Rab7 nucleotide binding, and thus regulate Rab7’s activity in endolysosomal trafficking and autophagy. It will also consider how bacterial pathogens manipulate Rab7 nucleotide binding to support intracellular invasion and immune evasion.
Highlights
Rab GTPases are essential for eukaryotic intracellular membrane and protein trafficking (Zhen and Stenmark, 2015)
This effect might be caused by TBC1D5-LC3A binding during autophagy (Roy et al, 2017), which sequesters TBC1D5 and permits Rab7 activation in the vicinity of the retromer
Rab7 and Ypt7p govern both endolysosomal trafficking and autophagy (Guerra and Bucci, 2016). They accomplish this by binding to a large and diverse set of effectors (Seals et al, 2000; Wurmser et al, 2000; Cantalupo et al, 2001; Jordens et al, 2001; Lazar et al, 2002; Pankiv et al, 2010; Sun et al, 2010). Before this can happen, the nucleotide-binding state of Rab7 and Ypt7p must be controlled in both time and space by the GEF and GAPs discussed here
Summary
Like all Rab GTPases, Rab cycles between an “active” GTPbound form that binds downstream effectors – e.g., the HOPS and retromer complexes and the dynactin-binding Rab-interacting lysosomal protein (RILP) – and an “inactive” GDP-bound form that cannot bind effectors. Accessory proteins regulate the nucleotide binding state of Rab: guanine nucleotide exchange factors (GEFs) stimulate exchange of bound GDP for GTP, resulting in Rab activation, whereas GTPase activating proteins (GAPs) boost Rab7’s GTP hydrolysis activity, thereby inactivating Rab. This review will discuss the GEF and GAPs that control Rab nucleotide binding, and regulate Rab7’s activity in endolysosomal trafficking and autophagy. It will consider how bacterial pathogens manipulate Rab nucleotide binding to support intracellular invasion and immune evasion
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