Abstract
Lysosomal distribution is linked to the role of lysosomes in many cellular functions, including autophagosome degradation, cholesterol homeostasis, antigen presentation, and cell invasion. Alterations in lysosomal positioning contribute to different human pathologies, such as cancer, neurodegeneration, and lysosomal storage diseases. Here we report the identification of a novel mechanism of lysosomal trafficking regulation. We found that the lysosomal transmembrane protein TMEM55B recruits JIP4 to the lysosomal surface, inducing dynein-dependent transport of lysosomes toward the microtubules minus-end. TMEM55B overexpression causes lysosomes to collapse into the cell center, whereas depletion of either TMEM55B or JIP4 results in dispersion toward the cell periphery. TMEM55B levels are transcriptionally upregulated following TFEB and TFE3 activation by starvation or cholesterol-induced lysosomal stress. TMEM55B or JIP4 depletion abolishes starvation-induced retrograde lysosomal transport and prevents autophagosome–lysosome fusion. Overall our data suggest that the TFEB/TMEM55B/JIP4 pathway coordinates lysosome movement in response to a variety of stress conditions.
Highlights
Lysosomal distribution is linked to the role of lysosomes in many cellular functions, including autophagosome degradation, cholesterol homeostasis, antigen presentation, and cell invasion
In agreement with previous reports, we found that TMEM55B co-localized with the lysosomal marker LAMP-1 (Fig. 1b, top) but not with early endosome marker hepatocyte growth factor-regulated tyrosine kinase substrate (HRS) (Fig. 1b, bottom)
Upon overexpression of GFP-TMEM55B, we observed a dramatic repositioning of lysosomes, changing from dispersed throughout the cell to tightly clustered in the cell center (Fig. 1c, top)
Summary
Lysosomal distribution is linked to the role of lysosomes in many cellular functions, including autophagosome degradation, cholesterol homeostasis, antigen presentation, and cell invasion. Overall our data suggest that the TFEB/TMEM55B/JIP4 pathway coordinates lysosome movement in response to a variety of stress conditions. Anterograde movement of lysosomes is regulated by the multi-subunit complex BORC, the small GTPase Arl[8], and its effector SKIP, which directly interacts with the kinesin light chain, linking lysosomes to the plusend-directed microtubule motor kinesin[19,20]. RILP interacts with the p150-glued subunit of dynactin, recruiting the minus-end-directed microtubule motor dynein to lysosomes[23,24,25]. Rab[34] and Rab[36] localize to the Golgi/TGN and directly interact with RILP, mediating tethering or anchoring of lysosomes to the Golgi[30,31] It is still unclear how Rabring[7] and Rapsyn may work in combination with microtubule motors[32,33]
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