Arl8 and SKIP Act Together to Link Lysosomes to Kinesin-1

• Published in: Developmental cell Vol. 21; no. 6; pp. 1171 - 1178
• Main Authors: Rosa-Ferreira, Cláudia, Munro, Sean
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 13.12.2011; Cell Press
• Subjects: Adaptor Proteins, Signal Transducing - antagonists & inhibitors; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; ADP-Ribosylation Factors - antagonists & inhibitors; ADP-Ribosylation Factors - genetics; ADP-Ribosylation Factors - metabolism; affinity chromatography; Alternative Splicing; Amino Acid Sequence; Animals; bacteria; Base Sequence; Biological and medical sciences; Cell differentiation, maturation, development, hematopoiesis; Cell physiology; Chlorocebus aethiops; COS Cells; Cytoplasm - metabolism; Fundamental and applied biological sciences. Psychology; guanosinetriphosphatase; HeLa Cells; Humans; Hydrogen-Ion Concentration; kinesin; Kinesins - metabolism; lysosomes; Lysosomes - metabolism; Lysosomes - physiology; microtubules; Molecular and cellular biology; Molecular Sequence Data; Movement; Protein Interaction Domains and Motifs; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; RNA, Small Interfering - genetics; Salmonella; Sequence Homology, Amino Acid; Short; Two-Hybrid System Techniques; vacuoles; Development; Molecular motor; Kinesin; Lysosome
• ISSN: 1534-5807; 1878-1551; 1878-1551
• DOI: 10.1016/j.devcel.2011.10.007

Lysosomes move bidirectionally on microtubules, and this motility can be stimulated by overexpression of the small GTPase Arl8. By using affinity chromatography, we find that Arl8-GTP binds to the soluble protein SKIP (SifA and kinesin-interacting protein, aka PLEKHM2). SKIP was originally identified as a target of the Salmonella effector protein SifA and found to bind the light chain of kinesin-1 to activate the motor on the bacteria's replicative vacuole. We show that in uninfected cells both Arl8 and SKIP are required for lysosomes to distribute away from the microtubule-organizing center. We identify two kinesin light chain binding motifs in SKIP that are required for lysosomes to accumulate kinesin-1 and redistribute to the cell periphery. Thus, Arl8 binding to SKIP provides a link from lysosomal membranes to plus-end-directed motility. A splice variant of SKIP that lacks a light chain binding motif does not stimulate movement, suggesting fine-tuning by alternative splicing. [Display omitted] ► The lysosomal GTPase Arl8 binds to the kinesin-1 linker SKIP ► SKIP and Arl8 are required for the normal intracellular distribution of lysosomes ► SKIP and Arl8 are required for the acid-induced centripetal movement of lysosomes ► SKIP contains a kinesin light chain binding site subject to alternative splicing