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Hermansky-Pudlak syndrome 6 protein (HPS6) has originally been identified as a subunit of the BLOC-2 protein complex that is involved in the biogenesis of lysosome-related organelles. Here, we demonstrate that HPS6 directly interacts with the dynactin p150(Glued) subunit of the dynein-dynactin motor complex and acts as cargo adaptor for the retrograde motor to mediate the transport of lysosomes from the cell periphery to the perinuclear region. Small interfering RNA (siRNA)-mediated knockdown of HPS6 in HeLa cells not only partially blocks centripetal movement of lysosomes but also causes delay in lysosome-mediated protein degradation. Moreover, lysosomal acidification and degradative capacity, as well as fusion between late endosomes and/or multivesicular bodies and lysosomes are also impaired when HPS6 is depleted, suggesting that perinuclear positioning mediated by the dynein-dynactin motor complex is required for lysosome maturation and activity. Our results have uncovered a so-far-unknown specific role for HPS6 in the spatial distribution of the lysosomal compartment.

HPS6 interacts with dynactin p150Glued to mediate retrograde trafficking and maturation of lysosomes