CoChat
Sign Up
Cited by 11Cellular transport and secretionParkinson's Disease Mechanisms and TreatmentsAutophagy in Disease and Therapy

The DOI matches its Crossref record; 2 of the 2 references it cites were found in a registry or an index.

Phosphorylation of Rab29 at Ser185 regulates its localization and role in the lysosomal stress response in concert with LRRK2

Open access
Komori, Tadayuki, Kuwahara, Tomoki, Fujimoto, Tetta, Sakurai, Maria, Koyama-Honda, Ikuko, Fukuda, Mitsunori, Iwatsubo, Takeshi·2023·Journal of Cell Science
DOI 10.1242/jcs.261003PMC PMC10399995

Published version of a preprint

Open this paper in CoChat — free accountOpen PDF

Abstract

Rab proteins are small GTPases that regulate a myriad of intracellular membrane trafficking events. Rab29 is one of the Rab proteins phosphorylated by leucine-rich repeat kinase 2 (LRRK2), a Parkinson's disease-associated kinase. Recent studies suggest that Rab29 regulates LRRK2, whereas the mechanism by which Rab29 is regulated remained unclear. Here, we report a novel phosphorylation in Rab29 that is not mediated by LRRK2 and occurs under lysosomal overload stress. Mass spectrometry analysis identified the phosphorylation site of Rab29 as Ser185, and cellular expression studies of phosphomimetic mutants of Rab29 at Ser185 unveiled the involvement of this phosphorylation in counteracting lysosomal enlargement. PKCα and PKCδ were deemed to be involved in this phosphorylation and control the lysosomal localization of Rab29 in concert with LRRK2. These results implicate PKCs in the lysosomal stress response pathway comprised of Rab29 and LRRK2, and further underscore the importance of this pathway in the mechanisms underlying lysosomal homeostasis.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1242/jcs.261003

Cites

2 of 2 references verified0 citation errors · 0 not checkable

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 50

  1. Babur, 2020, Phosphoproteomic quantitation and causal analysis reveal pathways in GPVI/ITAM-mediated platelet activation programs, Blood, 136, 2346, 10.1182/blood.2020005496 · DOI
  2. Bailey, 2014, A kinase inhibitor screen reveals protein kinase C-dependent endocytic recycling of ErbB2 in breast cancer cells, J. Biol. Chem., 289, 30443, 10.1074/jbc.M114.608992 · DOI
  3. Bailly, 1991, Phosphorylation of two small GTP-binding proteins of the Rab family by p34cdc2, Nature, 350, 715, 10.1038/350715a0 · DOI
  4. Belshaw, 1996, Controlling protein association and subcellular localization with a synthetic ligand that induces heterodimerization of proteins, Proc. Natl. Acad. Sci. USA, 93, 4604, 10.1073/pnas.93.10.4604 · DOI
  5. Binnington, 2016, Inhibition of Rab prenylation by statins induces cellular glycosphingolipid remodeling, Glycobiology, 26, 166, 10.1093/glycob/cwv084 · DOI
  6. Black, 2022, PKCα and PKCδ: friends and rivals, J. Biol. Chem., 298, 102194, 10.1016/j.jbc.2022.102194 · DOI
  7. Blom, 1999, Sequence and structure-based prediction of eukaryotic protein phosphorylation sites, J. Mol. Biol., 294, 1351, 10.1006/jmbi.1999.3310 · DOI
  8. Eguchi, 2018, LRRK2 and its substrate Rab GTPases are sequentially targeted onto stressed lysosomes and maintain their homeostasis, Proc. Natl. Acad. Sci. USA, 115, E9115, 10.1073/pnas.1812196115 · DOI
  9. Fujimoto, 2018, Parkinson's disease-associated mutant LRRK2 phosphorylates Rab7L1 and modifies trans-Golgi morphology, Biochem. Biophys. Res. Commun., 495, 1708, 10.1016/j.bbrc.2017.12.024 · DOI
  10. Gan-Or, 2012, Association of sequence alterations in the putative promoter of RAB7L1 with a reduced Parkinson disease risk, Arch Neurol-chicago, 69, 105, 10.1001/archneurol.2011.924 · DOI · Paper page
  11. Gomez, 2019, Membrane association but not identity is required for LRRK2 activation and phosphorylation of Rab GTPases, J. Cell Biol., 218, 4157, 10.1083/jcb.201902184 · DOI · Paper page
  12. Gschwendt, 1996, Inhibition of protein kinase C mu by various inhibitors. Differentiation from protein kinase c isoenzymes, FEBS Lett., 392, 77, 10.1016/0014-5793(96)00785-5 · DOI · Paper page
  13. Homma, 2021, Rab family of small GTPases: an updated view on their regulation and functions, FEBS J., 288, 36, 10.1111/febs.15453 · DOI
  14. Ito, 2016, Phos-tag analysis of Rab10 phosphorylation by LRRK2: a powerful assay for assessing kinase function and inhibitors, Biochem. J., 473, 2671, 10.1042/BCJ20160557 · DOI · Paper page
  15. Kluss, 2022, Directing LRRK2 to membranes of the endolysosomal pathway triggers RAB phosphorylation and JIP4 recruitment, Neurobiol. Dis., 170, 105769, 10.1016/j.nbd.2022.10576 · DOI
  16. Kuwahara, 2020, The emerging functions of LRRK2 and Rab GTPases in the endolysosomal system, Front. Neurosci., 14, 227, 10.3389/fnins.2020.00227 · DOI
  17. Kuwahara, 2016, LRRK2 and RAB7L1 coordinately regulate axonal morphology and lysosome integrity in diverse cellular contexts, Sci. Rep., 6, 29945, 10.1038/srep29945 · DOI · Paper page
  18. Kuwahara, 2020, Roles of lysosomotropic agents on LRRK2 activation and Rab10 phosphorylation, Neurobiol. Dis., 145, 105081, 10.1016/j.nbd.2020.105081 · DOI · Paper page
  19. Lazarou, 2012, Role of PINK1 binding to the TOM complex and alternate intracellular membranes in recruitment and activation of the E3 Ligase Parkin, Dev. Cell, 22, 320, 10.1016/j.devcel.2011.12.014 · DOI · Paper page
  20. Lin, 2017, Tyrosine phosphorylation of Rab7 by Src kinase, Cell. Signal., 35, 84, 10.1016/j.cellsig.2017.03.006 · DOI
  21. Liu, 2018, LRRK2 phosphorylates membrane-bound Rabs and is activated by GTP-bound Rab7L1 to promote recruitment to the trans Golgi network, Hum. Mol. Genet., 27, 385, 10.1093/hmg/ddx410 · DOI · Paper page
  22. Macleod, 2013, RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting and Parkinson's disease risk, Neuron, 77, 425, 10.1016/j.neuron.2012.11.033 · DOI · Paper page
  23. Madero-Pérez, 2018, RAB7L1-mediated relocalization of LRRK2 to the Golgi complex causes centrosomal deficits via RAB8A, Front. Mol. Neurosci., 11, 417, 10.3389/fnmol.2018.00417 · DOI · Paper page
  24. Mcgrath, 2021, LRRK2 binds to the Rab32 subfamily in a GTP-dependent manner via its armadillo domain, Small GTPases, 12, 133, 10.1080/21541248.2019.1666623 · DOI
  25. Nakamichi, 2006, Suppressive effect of simvastatin on interferon-β-induced expression of CC chemokine ligand 5 in microglia, Neurosci. Lett., 407, 205, 10.1016/j.neulet.2006.08.044 · DOI
  26. Ostermeier, 1999, Structural basis of rab effector specificity crystal structure of the small G protein Rab3A complexed with the effector domain of Rabphilin-3A, Cell, 96, 363, 10.1016/S0092-8674(00)80549-8 · DOI
  27. Pavarotti, 2012, Rab11 is phosphorylated by classical and novel protein kinase C isoenzymes upon sustained phorbol ester activation, Biol. Cell, 104, 102, 10.1111/boc.201100062 · DOI
  28. Pettersen, 2020, UCSF ChimeraX: structure visualization for researchers, educators, and developers, Protein Sci., 30, 70, 10.1002/pro.3943 · DOI
  29. Prevostel, 2000, Protein kinase C(alpha) actively downregulates through caveolae-dependent traffic to an endosomal compartment, J. Cell Sci., 113, 2575, 10.1242/jcs.113.14.2575 · DOI
  30. Purlyte, 2018, Rab29 activation of the Parkinson's disease–associated LRRK2 kinase, EMBO J., 37, 1, 10.15252/embj.201798099 · DOI · Paper page
  31. Saito, 2018, An alternative mitophagy pathway mediated by Rab9 protects the heart against ischemia, J. Clin. Invest., 129, 802, 10.1172/JCI122035 · DOI
  32. Sakurai, 2021, Experimental models of Parkinson's disease, Methods Mol. Biol., 2322, 63, 10.1007/978-1-0716-1495-2_7 · DOI
  33. Satake, 2009, Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease, Nat. Genet., 41, 1303, 10.1038/ng.485 · DOI
  34. Schindelin, 2012, Fiji: an open-source platform for biological-image analysis, Nat. Methods, 9, 676, 10.1038/nmeth.2019 · DOI · Paper page
  35. Shrivastava, 2022, Rabaptin5 acts as a key regulator for Rab7l1-mediated phagosome maturation process, Immunology, 165, 328, 10.1111/imm.13438 · DOI
  36. Singh, 2017, Protein kinase C-α and the regulation of diverse cell responses, Biomol Concepts, 8, 143, 10.1515/bmc-2017-0005 · DOI
  37. Sluijs, 1992, Reversible phosphorylation–-dephosphorylation determines the localization of rab4 during the cell cycle, EMBO J., 11, 4379, 10.1002/j.1460-2075.1992.tb05538.x · DOI
  38. Steger, 2016, Phosphoproteomics reveals that Parkinson's disease kinase LRRK2 regulates a subset of Rab GTPases, Elife, 5, e12813, 10.7554/eLife.12813 · DOI · Paper page
  39. Steger, 2017, Systematic proteomic analysis of LRRK2-mediated Rab GTPase phosphorylation establishes a connection to ciliogenesis, Elife, 6, e31012, 10.7554/eLife.31012 · DOI · Paper page
  40. Stein, 2012, The interaction properties of the human Rab GTPase family – a comparative analysis reveals determinants of molecular binding selectivity, PLoS One, 7, e34870, 10.1371/journal.pone.0034870 · DOI
  41. Svanbergsson, 2021, FRET-based screening identifies p38 MAPK and PKC inhibition as targets for prevention of seeded α-synuclein aggregation, Neurotherapeutics, 18, 1692, 10.1007/s13311-021-01070-1 · DOI
  42. Takahashi, 2022, Quantitative 3D correlative light and electron microscopy of organelle association during autophagy, Cell Struct. Funct., 47, 89, 10.1247/csf.22071 · DOI
  43. Takenouchi, 2005, Inhibitory effects of U73122 and U73343 on Ca2+ influx and pore formation induced by the activation of P2X7 nucleotide receptors in mouse microglial cell line, Biochim. Biophys. Acta, 1726, 177, 10.1016/j.bbagen.2005.08.001 · DOI
  44. Tsuboi, 2006, Rab3A and Rab27A cooperatively regulate the docking step of dense-core vesicle exocytosis in PC12 cells, J. Cell Sci., 119, 2196, 10.1242/jcs.02962 · DOI
  45. Tucci, 2010, Genetic variability at the PARK16 locus, Eur. J. Hum. Genet., 18, 1356, 10.1038/ejhg.2010.125 · DOI · Paper page
  46. Tzeng, 2017, Phosphorylation of Rab37 by protein kinase C alpha inhibits the exocytosis function and metastasis suppression activity of Rab37, Oncotarget, 8, 108556, 10.18632/oncotarget.20998 · DOI
  47. Vides, 2022, A feed-forward pathway drives LRRK2 kinase membrane recruitment and activation, Elife, 11, e79771, 10.7554/eLife.79771 · DOI · Paper page
  48. Wang, 2014, A role of Rab29 in the integrity of the trans-golgi network and retrograde trafficking of Mannose-6-phosphate receptor, PLoS One, 9, e96242, 10.1371/journal.pone.0096242 · DOI
  49. Waschbüsch, 2020, Phosphorylation of Rab GTPases in the regulation of membrane trafficking, Traffic, 21, 712, 10.1111/tra.12765 · DOI
  50. Zhu, 2022, Structural basis of human LRRK2 membrane recruitment and activation, Biorxiv 2022.04.26.489605, 10.1101/2022.04.26.489605 · DOI · Paper page

Metadata

Authors
Komori, T., Kuwahara, T., Fujimoto, T., Sakurai, M., Koyama-Honda, I., Fukuda, M., & Iwatsubo, T.
Affiliations
  • Tohoku University (JP)
  • The University of Tokyo (JP)
  • Graduate School and Faculty of Medicine, The University of Tokyo 3 Department of Biochemistry and Molecular Biology , , Tokyo 113-0033 , Japan
Corresponding author
  • Kuwahara, Tomoki
  • Iwatsubo, Takeshi
ORCID
Venue
Journal of Cell Science
Publisher
The Company of Biologists
Published
2023-07-15
Volume
136
Issue
14
ISSN
  • 0021-9533 (ISSN-L)
  • 1477-9137
DOI
10.1242/jcs.261003
PMC
PMC10399995
OpenAlex
W4382182786
Cited by
11
References
2
Citations by year
2026: 2 · 2025: 3 · 2024: 3 · 2023: 3
FWCI
1.59
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Cell Science (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Japan Society for the Promotion of Science (16K07039, 21J12881, 20J12819, 20H00525, 22H02949, 19K07816)
  • Japan Science and Technology Agency (JPMJER1702)
  • University of Tokyo
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
Keywords
Rab29, LRRK2, lysosomal homeostasis, lysosomal enlargement, protein kinase C alpha, protein kinase C delta, Rab GTPases, membrane trafficking, Parkinson's disease, phosphomimetic mutant
MeSH terms
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Lysosomes, Mutation, Phosphorylation, rab GTP-Binding Proteins

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review