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Optineurin mediates a negative regulation of Rab8 by the GTPase-activating protein TBC1D17
Vipul Vaibhava, Ananthamurthy Nagabhushana, Madhavi Latha Somaraju Chalasani, Cherukuri Sudhakar, Asha Kumari, Ghanshyam Swarup


Rab GTPases regulate various membrane trafficking pathways but the mechanisms by which GTPase-activating proteins recognise specific Rabs are not clear. Rab8 is involved in controlling several trafficking processes, including the trafficking of transferrin receptor from the early endosome to the 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 the 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. The activated GTP-bound form of Rab8 is localised to the tubules emanating from the endocytic recycling compartment. Through its catalytic activity, TBC1D17 inhibits recruitment of Rab8 to the tubules and reduces colocalisation of transferrin receptor and Rab8. Knockdown of optineurin or TBC1D17 results 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 endocytic recycling 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).


  • Funding

    This work was supported by a grant from the Department of Biotechnology, Government of India [grant number BT/PR10130/BRB/10/614/2008 to G.S.]. G.S. gratefully acknowledges the Department of Science and Technology, Government of India for a J C Bose National Fellowship. V.V. is recipient of a Senior Research Fellowship from the CSIR, New Delhi, India.

  • Supplementary material available online at

  • Accepted June 25, 2012.
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