TY - JOUR
T1 - Leucine-rich repeat kinase 2 regulates Sec16A at ER exit sites to allow ER-Golgi export
AU - Cho, Hyun Jin
AU - Yu, Jia
AU - Xie, Chengsong
AU - Rudrabhatla, Parvathi
AU - Chen, Xi
AU - Wu, Junbing
AU - Parisiadou, Loukia
AU - Liu, Guoxiang
AU - Sun, Lixin
AU - Ma, Bo
AU - Ding, Jinhui
AU - Liu, Zhihua
AU - Cai, Huaibin
N1 - Publisher Copyright:
© Published 2014. This article is a U.S. Government work and is in the public domain in the USA.
PY - 2014/10/16
Y1 - 2014/10/16
N2 - 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.
AB - 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.
KW - ER exit sites (ERES)
KW - ER-Golgi transport
KW - Leucine-rich repeat kinase 2 (LRRK2)
KW - Sec16A
KW - dendritic ERES (dERES)
UR - http://www.scopus.com/inward/record.url?scp=84911494334&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84911494334&partnerID=8YFLogxK
U2 - 10.15252/embj.201487807
DO - 10.15252/embj.201487807
M3 - Article
C2 - 25201882
AN - SCOPUS:84911494334
SN - 0261-4189
VL - 33
SP - 2314
EP - 2331
JO - EMBO Journal
JF - EMBO Journal
IS - 20
ER -