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

Hyun Jin Cho, Jia Yu, Chengsong Xie, Parvathi Rudrabhatla, Xi Chen, Junbing Wu, Loukia Parisiadou, Guoxiang Liu, Lixin Sun, Bo Ma, Jinhui Ding, Zhihua Liu*, Huaibin Cai

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

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. Synopsis Parkinson's disease (PD)-associated LRRK2 functions by associating with Sec16A at ER exit sites, facilitating COPII-mediated anterograde vesicle transport; a PD-associated LRRK2 mutant lacks this function. LRRK2 interacts and co-localizes with Sec16A at ER exit sites (ERES). LRRK2 regulates the attachment of Sec16A to ERES. LRRK2 regulates dendritic ERES and activity-dependent cell surface targeting of glutamate receptors in neurons. Parkinson's disease-related R1441C mutation compromises LRRK2's regulatory function on Sec16A and ER export. Parkinson's disease (PD)-associated LRRK2 functions by associating with Sec16A at ER exit sites, facilitating COPII-mediated anterograde vesicle transport; a PD-associated LRRK2 mutant lacks this function.

Original languageEnglish (US)
Pages (from-to)2314-2331
Number of pages18
JournalEMBO Journal
Volume33
Issue number20
DOIs
StatePublished - Oct 16 2014

Keywords

  • ER exit sites (ERES)
  • ER-Golgi transport
  • Leucine-rich repeat kinase 2 (LRRK2)
  • Sec16A
  • dendritic ERES (dERES)

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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