Rab small GTPases (∼60 genes in mammals) are the master regulators of intracellular membrane trafficking. Homma et al. establish a comprehensive collection of knockout epithelial cell lines for all the mammalian Rabs, revealing that Rab6 is required for basement membrane formation and soluble cargo secretion.

SummaryMelanoregulin (Mreg), a product of the dilute suppressor gene, has been implicated in the regulation of melanosome transport in mammalian epidermal melanocytes, given that Mreg deficiency was found to restore peripheral melanosome distribution from perinuclear melanosome aggregation in Rab27A-deficient melanocytes. However, the function of Mreg in melanosome transport has remained unclear. Here, we show that Mreg regulates microtubule-dependent retrograde melanosome transport through the dyneindynactin motor complex. Mreg interacted with the C-terminal domain of Rab-interacting lysosomal protein (RILP) and formed a complex with RILP and p150Glued (also known as dynactin subunit 1, DCTN1), a component of the dynein-dynactin motor complex, in cultured cells. Overexpression of Mreg, RILP or both, in normal melanocytes induced perinuclear melanosome aggregation, whereas knockdown of Mreg or functional disruption of the dynein-dynactin motor complex restored peripheral melanosome distribution in Rab27A-deficient melanocytes. These findings reveal a new mechanism by which the dynein-dynactin motor complex recognizes Mreg on mature melanosomes through interaction with RILP and is involved in the centripetal movement of melanosomes.

Highlights d The Parkinson's disease kinase LRRK2 interacts with the GARP complex at the TGN d LRRK2 stabilizes the binding of GARP to the t-SNARE Syntaxin-6 d LRRK2 regulates retrograde and anterograde transport in a kinase-dependent manner d Depletion of GARP intensifies neurodegeneration in C. elegans expressing G2019S-LRRK2

ABSTRACT. Rab small GTPases are highly conserved master regulators of membrane traffic in all eukaryotes. The same as the activation and inactivation of other small GTPases, the activation and inactivation of Rabs are tightly controlled by specific GEFs (guanine nucleotide exchange factors) and GAPs (GTPase-activating proteins), respectively. Although almost all Rab-GAPs reported thus far have a TBC (Tre-2/Bub2/Cdc16)/Rab-GAP domain in common, recent accumulating evidence has indicated the existence of a number of structurally unrelated types of Rab-GEFs, including DENN proteins, VPS9 proteins, Sec2 proteins, TRAPP complexes, heterodimer GEFs (Mon1-Ccz1, HPS1-HPS4 (BLOC-3 complex), Ric1-Rgp1 and Rab3GAP1/2), and other GEFs (e.g., REI-1 and RPGR). In this review article we provide an up-to-date overview of the structures and functions of all putative Rab-GEFs in mammals, with a special focus on their substrate Rabs, interacting proteins, associations with genetic diseases, and intracellular localizations.