Leucine-rich repeat kinase 2 regulates Sec16A at ER exit sites to allow ER-Golgi export

EMBO J. 2014 Oct 16;33(20):2314-31. doi: 10.15252/embj.201487807. Epub 2014 Sep 8.

Abstract

Leucine-rich repeat kinase 2 (LRRK2) has been associated with Parkinson's disease (PD) and other disorders. However, its normal physiological functions and pathogenic properties remain elusive. Here we show that LRRK2 regulates the anterograde ER-Golgi transport through anchoring Sec16A at the endoplasmic reticulum exit sites (ERES). LRRK2 interacted and co-localized with Sec16A, a key protein in the formation of ERES. Lrrk2 depletion caused a dispersion of Sec16A from ERES and impaired ER export. In neurons, LRRK2 and Sec16A showed extensive co-localization at the dendritic ERES (dERES) that locally regulate the transport of proteins to the dendritic spines. A loss of Lrrk2 affected the association of Sec16A with dERES and impaired the activity-dependent targeting of glutamate receptors onto the cell/synapse surface. Furthermore, the PD-related LRRK2 R1441C missense mutation in the GTPase domain interfered with the interaction of LRRK2 with Sec16A and also affected ER-Golgi transport, while LRRK2 kinase activity was not required for these functions. Therefore, our findings reveal a new physiological function of LRRK2 in ER-Golgi transport, suggesting ERES dysfunction may contribute to the pathogenesis of PD.

Keywords: ER exit sites (ERES); ER–Golgi transport; Leucine‐rich repeat kinase 2 (LRRK2); Sec16A; dendritic ERES (dERES).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • COP-Coated Vesicles / metabolism
  • Cell Line
  • Cells, Cultured
  • Dendritic Spines / metabolism
  • Endoplasmic Reticulum / metabolism*
  • Gene Expression Regulation
  • Genes, Reporter
  • Golgi Apparatus / metabolism*
  • Humans
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Mice
  • Models, Biological
  • Mutation, Missense
  • Parkinson Disease / enzymology*
  • Protein Interaction Mapping
  • Protein Transport
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Recombinant Fusion Proteins
  • Vesicular Transport Proteins / genetics
  • Vesicular Transport Proteins / metabolism*

Substances

  • Recombinant Fusion Proteins
  • SEC16A protein, human
  • Vesicular Transport Proteins
  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Protein-Serine-Threonine Kinases