The ALS8 protein VAPB interacts with the ER-Golgi recycling protein YIF1A and regulates membrane delivery into dendrites

EMBO J. 2013 Jul 17;32(14):2056-72. doi: 10.1038/emboj.2013.131. Epub 2013 Jun 4.


The vesicle-associated membrane protein (VAMP) associated protein B (VAPB) is an integral membrane protein localized to the endoplasmic reticulum (ER). The P56S mutation in VAPB has been linked to motor neuron degeneration in amyotrophic lateral sclerosis type 8 (ALS8) and forms ER-like inclusions in various model systems. However, the role of wild-type and mutant VAPB in neurons is poorly understood. Here, we identified Yip1-interacting factor homologue A (YIF1A) as a new VAPB binding partner and important component in the early secretory pathway. YIF1A interacts with VAPB via its transmembrane regions, recycles between the ER and Golgi and is mainly localized to the ER-Golgi intermediate compartments (ERGICs) in rat hippocampal neurons. VAPB strongly affects the distribution of YIF1A and is required for intracellular membrane trafficking into dendrites and normal dendritic morphology. When VAPB-P56S is present, YIF1A is recruited to the VAPB-P56S clusters and loses its ERGIC localization. These data suggest that both VAPB and YIF1A are important for ER-to-Golgi transport and that missorting of YIF1A may contribute to VAPB-associated motor neuron disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / metabolism*
  • Animals
  • Cells, Cultured
  • Dendrites / metabolism
  • Endoplasmic Reticulum / metabolism
  • Gene Knockdown Techniques
  • Golgi Apparatus / metabolism
  • Hippocampus / cytology
  • Hippocampus / metabolism
  • Membrane Proteins / chemistry
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Motor Neuron Disease / etiology
  • Motor Neuron Disease / metabolism
  • Multiprotein Complexes / chemistry
  • Multiprotein Complexes / metabolism
  • Mutant Proteins / chemistry
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neurons / metabolism
  • Protein Interaction Domains and Motifs
  • Protein Transport
  • Rats
  • Vesicular Transport Proteins / chemistry
  • Vesicular Transport Proteins / genetics
  • Vesicular Transport Proteins / metabolism*


  • Membrane Proteins
  • Multiprotein Complexes
  • Mutant Proteins
  • Nerve Tissue Proteins
  • VAPB protein, rat
  • Vesicular Transport Proteins
  • YIF1A protein, rat

Supplementary concepts

  • Amyotrophic Lateral Sclerosis 8