Defective relocalization of ALS2/alsin missense mutants to Rac1-induced macropinosomes accounts for loss of their cellular function and leads to disturbed amphisome formation

FEBS Lett. 2011 Mar 9;585(5):730-6. doi: 10.1016/j.febslet.2011.01.045. Epub 2011 Feb 17.

Abstract

Loss of ALS2/alsin function accounts for several recessive motor neuron diseases. ALS2 is a Rab5 activator and its endosomal localization is regulated by Rac1 via macropinocytosis. Here, we show that the pathogenic missense ALS2 mutants fail to be localized to Rac1-induced macropinosomes as well as endosomes, which leads to loss of the ALS2 function as a Rab5 activator on endosomes. Further, these mutants lose the competence to enhance the formation of amphisomes, the hybrid-organelle formed upon fusion between autophagosomes and endosomes. Thus, Rac1-induced relocalization of ALS2 might be crucial to exert the ALS2 function associated with the autophagy-endolysosomal degradative pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Endosomes / metabolism*
  • Guanine Nucleotide Exchange Factors / chemistry
  • Guanine Nucleotide Exchange Factors / genetics*
  • Guanine Nucleotide Exchange Factors / metabolism*
  • HeLa Cells
  • Humans
  • Mutant Proteins / metabolism*
  • Mutation, Missense / genetics*
  • Phagosomes / metabolism*
  • Phosphatidylinositol Phosphates / metabolism
  • Protein Binding
  • Protein Structure, Tertiary
  • Protein Transport
  • rab5 GTP-Binding Proteins / metabolism
  • rac1 GTP-Binding Protein / metabolism*

Substances

  • Guanine Nucleotide Exchange Factors
  • Mutant Proteins
  • Phosphatidylinositol Phosphates
  • rab5 GTP-Binding Proteins
  • rac1 GTP-Binding Protein