title: Leucine-rich repeat kinase 2 regulates Sec16A at ER exit sites to allow ER-Golgi export.
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.
authors.affiliation: Transgenics Section, Laboratory of Neurogenetics National Institute on Aging National Institutes of Health, Bethesda, MD, USA.
authors.forename: Hyun Jin
authors.initials: HJ
authors.lastname: Cho
authors.affiliation: Transgenics Section, Laboratory of Neurogenetics National Institute on Aging National Institutes of Health, Bethesda, MD, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Yu
authors.affiliation: Transgenics Section, Laboratory of Neurogenetics National Institute on Aging National Institutes of Health, Bethesda, MD, USA.
authors.forename: Chengsong
authors.initials: C
authors.lastname: Xie
authors.affiliation: Laboratory of Neurochemistry and Laboratory of Neurobiology National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
authors.forename: Parvathi
authors.initials: P
authors.lastname: Rudrabhatla
authors.affiliation: Transgenics Section, Laboratory of Neurogenetics National Institute on Aging National Institutes of Health, Bethesda, MD, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Transgenics Section, Laboratory of Neurogenetics National Institute on Aging National Institutes of Health, Bethesda, MD, USA.
authors.forename: Junbing
authors.initials: J
authors.lastname: Wu
authors.affiliation: Transgenics Section, Laboratory of Neurogenetics National Institute on Aging National Institutes of Health, Bethesda, MD, USA.
authors.forename: Loukia
authors.initials: L
authors.lastname: Parisiadou
authors.affiliation: Transgenics Section, Laboratory of Neurogenetics National Institute on Aging National Institutes of Health, Bethesda, MD, USA.
authors.forename: Guoxiang
authors.initials: G
authors.lastname: Liu
authors.affiliation: Transgenics Section, Laboratory of Neurogenetics National Institute on Aging National Institutes of Health, Bethesda, MD, USA.
authors.forename: Lixin
authors.initials: L
authors.lastname: Sun
authors.affiliation: Transgenics Section, Laboratory of Neurogenetics National Institute on Aging National Institutes of Health, Bethesda, MD, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Ma
authors.affiliation: Bioinformatics Core, Laboratory of Neurogenetics National Institute on Aging, Bethesda, MD, USA.
authors.forename: Jinhui
authors.initials: J
authors.lastname: Ding
authors.affiliation: Laboratory of Immunology, National Institute of Allergy and Infectious Diseases National Institutes of Health, Bethesda, MD, USA Institute of Biophysics Chinese Academy of Sciences, Beijing, China zhihualiu@ibp.ac.cn caih@mail.nih.gov.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Transgenics Section, Laboratory of Neurogenetics National Institute on Aging National Institutes of Health, Bethesda, MD, USA zhihualiu@ibp.ac.cn caih@mail.nih.gov.
authors.forename: Huaibin
authors.initials: H
authors.lastname: Cai
mesh_terms: D000818:Animals; D022181:COP-Coated Vesicles / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D049229:Dendritic Spines / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006056:Golgi Apparatus / Q000378:metabolism*; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D051379:Mice; D008954:Models, Biological; D020125:Mutation, Missense; D010300:Parkinson Disease / Q000201:enzymology*; D025941:Protein Interaction Mapping; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D011993:Recombinant Fusion Proteins; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D011993:Recombinant Fusion Proteins; C517555:SEC16A protein, human; D033921:Vesicular Transport Proteins; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases
keywords: ER exit sites (ERES); ER–Golgi transport; Leucine‐rich repeat kinase 2 (LRRK2); Sec16A; dendritic ERES (dERES)