Optineurin mediates negative regulation of Rab8 function by TBC1D17, a GTPase activating protein

Advance Online Publication August 1, 2012 doi: 10.1242/?jcs.102327 Rab GTPases regulate various membrane trafficking pathways but the mechanisms by which GTPase activating proteins recognize specific Rabs are not clear. Rab8 is involved in controlling several functions including the trafficking of transferrin receptor from early endosome to recycling endosome. Here we provide evidence to show that TBC1D17, a Rab GTPase activating protein, through its catalytic activity, regulates Rab8-mediated endocytic trafficking of transferrin receptor. Optineurin, a Rab8-binding effector protein, mediates interaction and colocalisation of TBC1D17 with Rab8. A non-catalytic region of TBC1D17 is required for direct interaction with optineurin. Co-expression of Rab8, but not other Rabs tested, rescues the inhibition of transferrin receptor trafficking by TBC1D17. Activated GTP-bound form of Rab8 is localized to the tubules emanating from the endocytic recycling compartment. Through its catalytic activity, TBC1D17 inhibits recruitment of Rab8 to the tubules and reduces colocalisation between transferrin receptor and Rab8. Knockdown of optineurin or TBC1D17 resulted in enhanced recruitment of Rab8 to the tubules. A glaucoma-associated mutant of optineurin, E50K causes enhanced inhibition of Rab8 by TBC1D17 resulting in defective endocytic recycling of transferrin receptor. Our results show that TBC1D17, through its interaction with optineurin, regulates Rab8-mediated endocytic recycling of transferrin receptor and recruitment of Rab8 to the tubules. We describe a mechanism of regulating a Rab GTPase by an effector protein (optineurin) that acts as an adaptor to bring together a Rab (Rab8) and its GTPase activating protein (TBC1D17).

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