Abstract
Secretory lysosomes are required for the specialised functions of various types of differentiated cells. In osteoclasts, the lysosomal proton pump V-ATPase (vacuolar-type ATPase) is targeted to the plasma membrane via secretory lysosomes and subsequently acidifies the extracellular compartment, providing optimal conditions for bone resorption. However, little is known about the mechanism underlying this trafficking of secretory lysosomes. Here, we demonstrate that the lysosome-specific a3 isoform of the V-ATPase a subunit plays an indispensable role in secretory lysosome trafficking, together with Rab7, a small GTPase involved in organelle trafficking. In osteoclasts lacking a3, lysosomes were not transported to the cell periphery, and Rab7 was not localised to lysosomes but diffused throughout the cytoplasm. Expression of dominant-negative (GDP-bound form) Rab7 inhibited lysosome trafficking in wild-type cells. Furthermore, a3 directly interacted with the GDP-bound forms of Rab7 and Rab27A. These findings reveal a novel role for the proton pump V-ATPase in secretory lysosome trafficking and an unexpected mechanistic link with Rab GTPases.
Highlights
Secretory lysosomes are indispensable in osteoclasts, which are involved in bone resorption[3,4,12]
We demonstrate that the a3 isoform of V-ATPase has dual function in osteoclasts: it is essential for lacunae acidification, and for secretory lysosome trafficking via Rab protein recruitment
Finger-like folds of the ruffled border were clearly identified (Fig. 1c). These results indicate that the a3 isoform is not essential for formation of lacunae
Summary
Secretory lysosomes are indispensable in osteoclasts, which are involved in bone resorption[3,4,12]. Six of the thirteen subunits that form mammalian V-ATPases have multiple isoforms specific to an organelle and/or type of differentiated cells[24,25,26]. Reduced expression of Rab[7] and Rab27A in osteoclasts results in impaired bone resorption, indicating that these proteins are involved in lysosomal secretion[39,40]. The mechanism by which individual Rab proteins are recruited to specific organelles/vesicles remains to be elucidated. We demonstrate that the a3 isoform of V-ATPase has dual function in osteoclasts: it is essential for lacunae acidification, and for secretory lysosome trafficking via Rab protein recruitment. We elucidate the mechanism underlying lysosome trafficking, demonstrating an unexpected link between the V-ATPase a3 isoform and Rab small GTPases
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