ARL13B TRAFFICKING

Role of Arl13b in endocytic trafficking

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 Obiettivo del progetto (Objective)

'To move cargo between specific membrane-bound intracellular compartments, eukaryotic cells have evolved numerous mechanisms of membrane trafficking regulation. We found that CD1a, an MHC Class I-like lipid antigen presenting molecule follows an endocytic recycling pathway similar to that used by MHC Class I and other cargo internalized independently of clathrin. In an attempt to discover new regulators of this pathway, we screened a shRNA library for changes in CD1a surface expression and we found that the small GTPase Arl13b could be involved in the regulation of endocytic trafficking. The knock-down of Arl13b caused the clustering of early endosomes and the accumulation in this organelle of recycling cargo, such as transferrin, and also cargo destined for late endosomes and lysosomes, such as dextran. Moreover, the recycling rate of CD1a was decreased when Arl13b was knocked-down. Together, these results indicate that Arl13b regulates a sorting step from the early/sorting endosome. Arl13b belongs to the Arf-like (Arl) family of small GTPases, which remains poorly characterized. By uncovering its function we will shed light on the regulatory functions of this family of proteins. Future studies will focus on finding Arl13b effectors, determining if Arl13b binds to the cytoskeleton like other Arls, and also establishing the role of this protein in the primary cilium, a structure where Arl13b localizes prominently.'

Introduzione (Teaser)

Transporting materials from outside the cell and subsequent intracellular trafficking is an important cell function. European researchers have investigated a new molecular player that also has a crucial role in cell cilia maintenance.

Descrizione progetto (Article)

Cilia, hair-like projections on the cell surface, play a range of roles in mammals including chemical sensation and signal transduction. An enzyme, ADP-ribosylation factor-like protein 13B (Arl13b) is known to play a role in cilia formation and their maintenance.

In humans, mutations in Arl13b cause Joubert Syndrome, a rare disorder that affects the cerebellum. Symptoms include lack of muscle tone and abnormal breathing patterns with moderate mental retardation.

Recent research has indicated that Arl13b may play a significant role in trafficking of materials in membrane-bound vesicles (endocytic trafficking). The EU-funded 'Role of Arl13b in endocytic trafficking' (ARL13B TRAFFICKING) project aimed to determine the functional and regulatory role of this guanosine-5'-triphosphate (GTP)ase enzyme.

Using gene silencing techniques, the project scientists found that Arl13b is likely to control a sorting step from the early endosome. Material destined for late endosomes such as dextran was found to accumulate in the absence of Arl13b. Moreover, the recycling of molecules dependent on this endocytic mechanism slowed down.

Looking for effectors or regulators of Arl13b, the team identified non-muscle myosin heavy chain IIA, or Myh9. Arl13b interacts with Myh9 to lock onto actin. An important scaffolding protein, actin is crucial for cilia function and endocytosis.

The scientists identified another effector for Arl13b, a subunit of the exocyst. Significantly, the exocyst complex is involved in tethering vesicles from the Golgi Apparatus and the endocytic recycling compartment. Recent research has shown that the exocyst is required for ciliogenesis and proper localisation of ciliary cargo. The researchers argue that this interaction is linked to regulation of ciliary cargo by Ar1l3b.

ARL13B TRAFFICKING research has discovered two major regulators of a protein important in many cell functions but particularly in cell cargo movement. Mutations of the protein cause disorders linked to primary cilia structure. Uncovering the molecular mechanisms could form the basis of targeted therapies for related disorders.