Membrane association but not identity is required for LRRK2 activation and phosphorylation of Rab GTPases

TY - JOUR

T1 - Membrane association but not identity is required for LRRK2 activation and phosphorylation of Rab GTPases

AU - Gomez, Rachel C.

AU - Wawro, Paulina

AU - Lis, Paweł

AU - Alessi, Dario

AU - Pfeffer, Suzanne R.

N1 - © 2019 Gomez et al.

PY - 2019/12/2

Y1 - 2019/12/2

N2 - LRRK2 kinase mutations cause familial Parkinson’s disease and increased phosphorylation of a subset of Rab GTPases. Rab29 recruits LRRK2 to the trans Golgi and activates it there, yet some of LRRK2’s major Rab substrates are not on the Golgi. We sought to characterize the cell biology of LRRK2 activation Unlike other Rab family members, we show that Rab29 binds nucleotide weakly, is poorly prenylated, and is not bound to GDI in cytosol; nevertheless, Rab29 only activates LRRK2 when it is membrane-bound and GTP-bound. Mitochondrially anchored, GTP-bound Rab29 is both a LRRK2 substrate and activator, and it drives accumulation of active LRRK2 and phospho-Rab10 on mitochondria. Importantly, mitochondrially anchored LRRK2 is much less capable of phosphorylating plasma membrane-anchored Rab10 than soluble LRRK2. These data support a model in which LRRK2 associates with and dissociates from distinct membrane compartments to phosphorylate Rab substrates; if anchored, LRRK2 can modify misdelivered Rab substrates that then become trapped there because GDI cannot retrieve them.

AB - LRRK2 kinase mutations cause familial Parkinson’s disease and increased phosphorylation of a subset of Rab GTPases. Rab29 recruits LRRK2 to the trans Golgi and activates it there, yet some of LRRK2’s major Rab substrates are not on the Golgi. We sought to characterize the cell biology of LRRK2 activation Unlike other Rab family members, we show that Rab29 binds nucleotide weakly, is poorly prenylated, and is not bound to GDI in cytosol; nevertheless, Rab29 only activates LRRK2 when it is membrane-bound and GTP-bound. Mitochondrially anchored, GTP-bound Rab29 is both a LRRK2 substrate and activator, and it drives accumulation of active LRRK2 and phospho-Rab10 on mitochondria. Importantly, mitochondrially anchored LRRK2 is much less capable of phosphorylating plasma membrane-anchored Rab10 than soluble LRRK2. These data support a model in which LRRK2 associates with and dissociates from distinct membrane compartments to phosphorylate Rab substrates; if anchored, LRRK2 can modify misdelivered Rab substrates that then become trapped there because GDI cannot retrieve them.

UR - https://www.scopus.com/pages/publications/85076060990

U2 - 10.1083/jcb.201902184

DO - 10.1083/jcb.201902184

M3 - Article

C2 - 31624137

SN - 0021-9525

VL - 218

SP - 4157

EP - 4170

JO - Journal of Cell Biology

JF - Journal of Cell Biology

IS - 12

ER -