ARL3, a small GTPase with a functionally conserved role in primary cilia and immune synapses

Figures & data

Figure 1. Signalling pathways in the primary cilium. Schematic diagram demonstrating some of the signalling pathways transduced by the primary cilium. Mechanical and chemical extracellular signals are sensed by proteins in the membrane of the cilium, which are then transduced into the cell to activate a variety of intracellular pathways. Figure adapted from [32]. Hh, Hedgehog; PCP, planar cell polarity; PDGFα, Platelet Derived Growth Factor Subunit alpha; Shh, Sonic Hedgehog

Figure 2. Proposed interaction and function of ARL3 in the cilium

ARL3-GDP has a high concentration in the cell whereas ARL3-GTP has a high concentration in the cilium; this is thought to be achieved by the localization of ARL13B in the cilium, and RP2 outside the cilium. This would create a concentration gradient for movement of ARL3-GDP/GTP in and out of the cilium to maintain homoeostasis. In the cilium, ARL13B hydrolyses GDP-bound ARL3 into active ARL3-GTP. Trafficking of cargo and its carrier into the cilium allows interaction with ARL3-GTP which causes release of the cargo from the carrier. The carrier then passes back into the cell to bind other cargo, along its concentration gradient. ARL3-GTP also exits the cilium down its concentration gradient into the cell where it interacts with RP2 and is converted into ARL3-GDP.

Figure 3. ARL3 missense mutations at a conserved site affects the interaction of ARL3 with ARL13B

Ribbon and surface representation of ARL3 protein (in grey) interacting with ARL13B protein in violet. ARL3 Arg148 and ARL13B Glu86 side chains are shown as sticks.

Figure 4. A common role for ARL3, ARL13B and UNC119A in the primary cilia and the immunological synapse

A model of transporting prenylated and myristoylated proteins to the primary cilium (on the left) and a canonical immune synapse on the right, where docking of the centriole at the plasma membrane and polarization of the Golgi are common features. ARL13B, the ARL3 GEF, is enriched in both the cilium and immune synapse, which results in a high concentration of active GTP loaded ARL3. UNC119A, UNC119B or PDE6D solubilize the lipid modified cargo by forming a complex with the cargo and sequestering the hydrophobic lipid group. The complex is then disrupted by ARL3GTP resulting in the exposure of the lipid group which then associates with the ciliary or immune synapse membranes. Phosphorylation of the LCK at tyrosine 394 interferes with the interaction with UNC119A.

D’Angelo A, Franco B. The dynamic cilium in human diseases. PathoGenetics. 2009;2(1):3.

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