Leucine-rich repeat kinase 2 regulates Sec16A at ER exit sites to allow ER-Golgi export.
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.
['Cho|Hyun Jin|HJ|', 'Yu|Jia|J|', 'Xie|Chengsong|C|', 'Rudrabhatla|Parvathi|P|', 'Chen|Xi|X|', 'Wu|Junbing|J|', 'Parisiadou|Loukia|L|', 'Liu|Guoxiang|G|', 'Sun|Lixin|L|', 'Ma|Bo|B|', 'Ding|Jinhui|J|', 'Liu|Zhihua|Z|', 'Cai|Huaibin|H|']
D000818:Animals D022181:COP-Coated Vesicles D002460:Cell Line D002478:Cells, Cultured D049229:Dendritic Spines D004721:Endoplasmic Reticulum D005786:Gene Expression Regulation D017930:Genes, Reporter D006056:Golgi Apparatus D006801:Humans D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 D051379:Mice D008954:Models, Biological D020125:Mutation, Missense D010300:Parkinson Disease D025941:Protein Interaction Mapping D017346:Protein Serine-Threonine Kinases D021381:Protein Transport D011993:Recombinant Fusion Proteins D033921:Vesicular Transport Proteins
Sec16A dendritic ERES (dERES) ER exit sites (ERES) ER–Golgi transport Leucine‐rich repeat kinase 2 (LRRK2)