Arl8 and SKIP act together to link lysosomes to kinesin-1

Dev Cell. 2011 Dec 13;21(6):1171-8. doi: 10.1016/j.devcel.2011.10.007.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP-Ribosylation Factors / antagonists & inhibitors
  • ADP-Ribosylation Factors / genetics
  • ADP-Ribosylation Factors / metabolism*
  • Adaptor Proteins, Signal Transducing / antagonists & inhibitors
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Alternative Splicing
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • COS Cells
  • Chlorocebus aethiops
  • Cytoplasm / metabolism
  • HeLa Cells
  • Humans
  • Hydrogen-Ion Concentration
  • Kinesin / metabolism*
  • Lysosomes / metabolism*
  • Lysosomes / physiology
  • Molecular Sequence Data
  • Movement
  • Protein Interaction Domains and Motifs
  • RNA, Small Interfering / genetics
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Sequence Homology, Amino Acid
  • Two-Hybrid System Techniques

Substances

  • Adaptor Proteins, Signal Transducing
  • KIF5B protein, human
  • RNA, Small Interfering
  • Recombinant Fusion Proteins
  • SKIP protein, human
  • ARL5B protein, human
  • Kinesin
  • ADP-Ribosylation Factors