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

    Research output: Contribution to journalArticle

    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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  • Cite this

    Cho, H. J., Yu, J., Xie, C., Rudrabhatla, P., Chen, X., Wu, J., Parisiadou, L., Liu, G., Sun, L., Ma, B., Ding, J., Liu, Z., & Cai, H. (2014). Leucine-rich repeat kinase 2 regulates Sec16A at ER exit sites to allow ER-Golgi export. EMBO Journal, 33(20), 2314-2331. https://doi.org/10.15252/embj.201487807