The endocytic recycling pathway is controlled by the ADP-ribosylated GTPase Rab14

The GTPase Rab14 is localized at the trans-Golgi network and at the intermediate compartment associated to sorting/recycling endosomes-like structures of the transferrin- recycling pathway: as other Rab family members, it is involved in the regulation of intracellular vesicle trafficking, though its...

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Bibliographic Details
Published inbioRxiv
Main Authors Corteggio, Annunziata, Matteo Lo Monte, Schembri, Laura, Dathan, Nina, Simone Di Paola, Grimaldi, Giovanna, Corda, Daniela
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 26.11.2022
Subjects
ADP-ribosylation
Defective mutant
Endosomes
Glutamic acid
Golgi apparatus
Guanosine triphosphatases
Post-translation
Protein turnover
Ribosylation
Transferrin
Transferrin receptors
Vesicles
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Summary:The GTPase Rab14 is localized at the trans-Golgi network and at the intermediate compartment associated to sorting/recycling endosomes-like structures of the transferrin- recycling pathway: as other Rab family members, it is involved in the regulation of intracellular vesicle trafficking, though its role and functional relationship with effector/endosomal proteins is still incomplete. We have analysed whether post-translational modifications could affect Rab14 activity: the results obtained define mono-ADP-ribosylation (MARylation) as the yet-unknown Rab14 modification, catalysed by the ADP-ribosyltransferase PARP12, which specifically modifies glutamic acid residues in position 159/162. This modification is essential for the Rab14- dependent endosome progression. Accordingly, recycling of the transferrin receptor is inhibited when MARylation of Rab14 is prevented by PARP12 knocking-down or inhibition, or by overexpression of Rab14 ADP-ribosylation-defective mutant. Under these conditions, Rab14 and transferrin receptors are withheld at the cell periphery at the level of the Rab4- RUFY1-positive sorting endosomes, indicating that the interaction of Rab14 with the dual effectors RUFY and then FIP1c (which specifically binds both Rab11 and Rab14) determines the progression between the Rab4-RUFY- and Rab11-FIP1c-specific vesicles. Therefore Rab14-MARylation determines the sequential binding of this GTPase to RUFY and FIP1c, thus controlling endosome progression (i.e., transferrin receptors recycling) through the Rab4- , Rab14- and Rab11-specific vesicles. This identifies a Rab14-specific compartment of the recycling pathway and a crucial enzymatic reaction amenable to pharmacological control.Competing Interest StatementThe authors have declared no competing interest.
DOI:10.1101/2022.11.26.517555