PXD045671-1

PXD045671 is an original dataset announced via ProteomeXchange.

Title	Parkinson’s VPS35[D620N] mutation induces LRRK2 mediated lysosomal association of RILPL1 and TMEM55B
Description	The Parkinson’s VPS35[D620N] mutation causes lysosome dysfunction enhancing LRRK2 kinase activity. We find the VPS35[D620N] mutation alters expression of ~350 lysosomal proteins and stimulates LRRK2 recruitment and phosphorylation of Rab proteins at the lysosome. This recruits the phosphoRab effector protein RILPL1 to the lysosome where it binds to the lysosomal integral membrane protein TMEM55B. We identify highly conserved regions of RILPL1 and TMEM55B that interact and design mutations that block binding. In mouse fibroblasts, brain, and lung, we demonstrate that the VPS35 [D620N] mutation reduces RILPL1 levels, in a manner reversed by LRRK2 inhibition. Knock-out of RILPL1 enhances phosphorylation of Rab substrates and knock-out of TMEM55B increases RILPL1 levels. The lysosomotropic agent LLOMe, also induced LRRK2 kinase mediated association of RILPL1 to the lysosome, but to a lower extent than the D620N mutation. Our study uncovers a pathway through which dysfunctional lysosomes resulting from the VPS35[D620N] mutation recruit and activate LRRK2 on the lysosomal surface, driving assembly of the RILPL1-TMEM55B complex.
HostingRepository	PRIDE
AnnounceDate	2023-11-08
AnnouncementXML	Submission_2023-11-08_04:15:30.457.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Raja SekharNirujogi
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; deamidated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2023-09-25 13:39:32	ID requested
⏵ 1	2023-11-08 04:15:30	announced
2	2024-10-22 06:13:50	announced	2024-10-22: Updated project metadata.

Dataset with its publication pending

submitter keyword: Parkinson's disease, LRRK2, Lysosome, Proteomics

Prof. Dario R.Alessi
contact affiliation	MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, DUNDEE, DD1 5EH, United Kingdom
contact email	d.r.alessi@dundee.ac.uk
lab head
Raja SekharNirujogi
contact affiliation	MRC Protein Phosphorylation Unit, university of Dundee
contact email	rnirujogi@dundee.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD045671
     1. Label: PRIDE project
     2. Name: Parkinson’s VPS35[D620N] mutation induces LRRK2 mediated lysosomal association of RILPL1 and TMEM55B