LRRK2 Modulates the Exocyst Complex Assembly by Interacting with Sec8

Cells. 2021 Jan 20;10(2):203. doi: 10.3390/cells10020203.

Abstract

Mutations in LRRK2 play a critical role in both familial and sporadic Parkinson's disease (PD). Up to date, the role of LRRK2 in PD onset and progression remains largely unknown. However, experimental evidence highlights a critical role of LRRK2 in the control of vesicle trafficking, likely by Rab phosphorylation, that in turn may regulate different aspects of neuronal physiology. Here we show that LRRK2 interacts with Sec8, one of eight subunits of the exocyst complex. The exocyst complex is an evolutionarily conserved multisubunit protein complex mainly involved in tethering secretory vesicles to the plasma membrane and implicated in the regulation of multiple biological processes modulated by vesicle trafficking. Interestingly, Rabs and exocyst complex belong to the same protein network. Our experimental evidence indicates that LRRK2 kinase activity or the presence of the LRRK2 kinase domain regulate the assembly of exocyst subunits and that the over-expression of Sec8 significantly rescues the LRRK2 G2019S mutant pathological effect. Our findings strongly suggest an interesting molecular mechanism by which LRRK2 could modulate vesicle trafficking and may have important implications to decode the complex role that LRRK2 plays in neuronal physiology.

Keywords: LRRK2; Parkinson’s disease; Sec8; exocyst complex.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • HEK293 Cells
  • Humans
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / metabolism*
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Multiprotein Complexes / metabolism*
  • PC12 Cells
  • Protein Binding
  • Rats
  • Vesicular Transport Proteins / metabolism*

Substances

  • EXOC4 protein, human
  • Exoc4 protein, rat
  • Membrane Proteins
  • Multiprotein Complexes
  • Sec8l1 protein, mouse
  • Vesicular Transport Proteins
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2