Rab22A recruits BLOC ‐1 and BLOC ‐2 to promote the biogenesis of recycling endosomes

Abstract

Recycling endosomes (REs) are transient endosomal tubular intermediates of early/sorting endosomes (E/SEs) that function in cargo recycling to the cell surface and deliver the cell type‐specific cargo to lysosome‐related organelles such as melanosomes in melanocytes. However, the mechanism of RE biogenesis is largely unknown. In this study, by using an endosomal Rab‐specific RNAi screen, we identified Rab22A as a critical player during RE biogenesis. Rab22A‐knockdown results in reduced RE dynamics and concurrent cargo accumulation in the E/SEs or lysosomes. Rab22A forms a complex with BLOC‐1, BLOC‐2 and the kinesin‐3 family motor KIF13A on endosomes. Consistently, the RE‐dependent transport defects observed in Rab22A‐depleted cells phenocopy those in BLOC‐1‐/BLOC‐2‐deficient cells. Further, Rab22A depletion reduced the membrane association of BLOC‐1/BLOC‐2. Taken together, these findings suggest that Rab22A promotes the assembly of a BLOC‐1‐BLOC‐2‐KIF13A complex on E/SEs to generate REs that maintain cellular and organelle homeostasis.

Rab10 regulates tubular endosome formation through KIF13A/B motors

“…S3D). Rab22A may have a similar function to Rab10, because an interaction between Rab22A and KIF13A has been reported during the course of preparing this manuscript for publication (Shakya et al, 2018). However, since disruption of tubular endosomes in Rab10-KO cells and Rab22-DKO cells was not rescued by overexpression of Rab22A and Rab10, respectively (Fig.…”

The road to lysosome‐related organelles: Insights from Hermansky‐Pudlak syndrome and other rare diseases

“…In melanocytes and HeLa cells, BLOC‐1 associates with the kinesin‐3 motor, KIF13A, perhaps linking membrane tubules to the microtubule cytoskeleton, and promotes actin rearrangements to stabilize and elongate tubules, and in HeLa cells (but perhaps not in melanocytes) to sever them . Some of these interactions may be coordinated by the small GTPase RAB22 . Consistent with a role for BLOC‐1 in regulating the actin cytoskeleton, comparative proteomic analyses of brains from wild‐type or BLOC‐1‐deficient mice suggest that loss of BLOC‐1 function results in depletion of the actin nucleation complex, Arp2/3, and that this interaction is important for actin dynamics in HEK293 cells and neuronal plasticity at D melanogaster synapses .…”

“…How BLOC‐2 promotes the contact of recycling endosomal tubules with melanosomes is unknown, but might reflect either a classical membrane tethering function or a stabilizing function for the membrane tubules along microtubules or with the KIF13A kinesin‐3 motor. Consistently, pull‐down experiments suggest that the stalk domain of KIF13A might interact with BLOC‐2, perhaps in association with RAB22 . When overexpressed in HEK293 cells, the HPS6 subunit was found to coprecipitate with the dynactin p150glued subunit, but it is not clear if this reflects a physiological function of intact BLOC‐2.…”

Rab22a is a novel prognostic marker for cell progression in breast cancer

“…A number of studies on the possible function of Rab22a have emerged during recent years (25,26). However, the role of Rab22a in Bc has not been discussed as much.…”

“…Defective vesicular trafficking of growth factor receptors has been found to be a manifold hallmark of cancerous cells (32). Rab22a has been reported to control the trafficking of recycling endosomes comprising clathrin-dependent factors, such as epidermal growth factor receptor, transferrin receptor protein 2, copper-transporting ATPase 1 and glucose transporter 4, as well as clathrin-independent factors, such as MHc-I, β2-adrenergic receptor and integrin b1 receptor are endocytosed cargoes to the cell surface in non-melanocytes (26).…”