Distinct Roles for RAB10 and RAB29 in Pathogenic LRRK2-Mediated Endolysosomal Trafficking Alterations.
Endosomes
/ metabolism
Epidermal Growth Factor
/ metabolism
Gene Knockdown Techniques
Golgi Apparatus
/ metabolism
HeLa Cells
Humans
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
/ genetics
Lysosomes
/ metabolism
Mutation
/ genetics
Protein Transport
Proteolysis
rab GTP-Binding Proteins
/ metabolism
rab4 GTP-Binding Proteins
/ metabolism
rab7 GTP-Binding Proteins
Golgi
LRRK2
Parkinson’s disease
RAB10
RAB29
endolysosome
Journal
Cells
ISSN: 2073-4409
Titre abrégé: Cells
Pays: Switzerland
ID NLM: 101600052
Informations de publication
Date de publication:
17 07 2020
17 07 2020
Historique:
received:
23
06
2020
revised:
12
07
2020
accepted:
13
07
2020
entrez:
26
7
2020
pubmed:
28
7
2020
medline:
5
3
2021
Statut:
epublish
Résumé
Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) cause familial Parkinson's disease, and sequence variations are associated with the sporadic form of the disease. LRRK2 phosphorylates a subset of RAB proteins implicated in secretory and recycling trafficking pathways, including RAB8A and RAB10. Another RAB protein, RAB29, has been reported to recruit LRRK2 to the Golgi, where it stimulates its kinase activity. Our previous studies revealed that G2019S LRRK2 expression or knockdown of RAB8A deregulate epidermal growth factor receptor (EGFR) trafficking, with a concomitant accumulation of the receptor in a RAB4-positive recycling compartment. Here, we show that the G2019S LRRK2-mediated EGFR deficits are mimicked by knockdown of RAB10 and rescued by expression of active RAB10. By contrast, RAB29 knockdown is without effect, but expression of RAB29 also rescues the pathogenic LRRK2-mediated trafficking deficits independently of Golgi integrity. Our data suggest that G2019S LRRK2 deregulates endolysosomal trafficking by impairing the function of RAB8A and RAB10, while RAB29 positively modulates non-Golgi-related trafficking events impaired by pathogenic LRRK2.
Identifiants
pubmed: 32709066
pii: cells9071719
doi: 10.3390/cells9071719
pmc: PMC7407826
pii:
doi:
Substances chimiques
Rab29 protein, human
0
rab7 GTP-Binding Proteins
0
Epidermal Growth Factor
62229-50-9
LRRK2 protein, human
EC 2.7.11.1
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
EC 2.7.11.1
Rab10 protein, human
EC 3.6.1.-
rab GTP-Binding Proteins
EC 3.6.5.2
rab4 GTP-Binding Proteins
EC 3.6.5.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
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