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Data availability
All data presented in this study are shown in Fig. 1 and Extended Data Figs. 1 and 2. Raw data are available in the source data file. The MS raw data have been deposited in the PRIDE database under accession no. PXD055546. Source data are provided with this paper.
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Acknowledgements
We thank Interline Therapeutics for their support, and researchers at Interline and the University of Dundee for useful discussions. We thank the Biological Resources Unit, and the Flow Cytometry and Cell Sorting and Fingerprints Proteomics facilities, at the University of Dundee for technical support, and Dr. M. Gierlinski, Data Analysis Group, University of Dundee, for plotting Fig. 1e. M.S. is supported by the Wellcome Trust and Royal Society (Sir Henry Dale Fellowship, no. 206246/Z/17/A). The data shown in Fig. 1a–d and Extended Data Fig. 1a were funded by Interline Therapeutics. M.M.S. is funded by Tenovus Scotland. The funders had no role in the conceptualization, design, data collection and analysis, or preparation of the manuscript.
Author information
Authors and Affiliations
Contributions
A.T., D.D., M.M.S., A.S.C. and R.P. performed the experiments and analyzed the data. T.H. performed the experiments. T.M. analyzed the data. M.H.M. provided the reagents and human neutrophils and organoids, and analyzed the data. A.T. and M.S. wrote the manuscript with input from the other authors.
Corresponding author
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Competing interests
M.S. receives research funding from AstraZeneca and Interline Therapeutics. M.H.M. receives research funding from beLAB1407 (Evotec and Bristol Myers Squibb). A.T. is currently an employee of Amphista Therapeutics. The other authors declare no competing interests.
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Peer review information
Nature Immunology thanks Zhenyu Yue and the other, anonymous reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Ioana Staicu in collaboration with the Nature Immunology editorial team.
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Extended data
Extended Data Fig. 1 LRRK2 is not detected in Paneth cells from EGFP-Lrrk2KI/KI mice.
a) Spleens were dissected from Lrrk2+/+ and Lrrk2-/- littermate mice used to generate ileal organoids shown in Fig. 1b–d, and snap frozen until use. 40 µg of homogenized lysates were loaded and Immunoblotting done for LRRK2 pSer935, LRRK2, total Rab10, pT73 Rab10 and loading controls α-tubulin are shown (n = 2 mice per genotype). A549 cell lysates were used as controls as in Fig. 1c. b) Representative flow cytometric plots showing the gating strategy to identify CD24+CD45– epithelial cells (includes Paneth cells), CD24–CD45–EpCAM+SSClo epithelial cells, and CD24+CD45+ cells (immune cells) isolated from ileal crypts. Graph shows EGFP-LRRK2 geometric mean fluorescence intensities above background in EGFP-Lrrk2KI/KI mice, calculated by subtracting the mean autofluorescence of the respective cell type measured in WT littermate mice (n = 4). Means and individual biological replicates shown. Data representative of 2 experiments.
Extended Data Fig. 2 LRRK2 is not involved in NOD2 signalling in MODE-K cells.
a) MODE-K cells treated with TLR2 and NOD2 agonists Pam3CSK4 (1 µg/ml), MDP (10 µg/mL) with or without LRRK2 inhibitor MLi-2 (100 nM) for 24 h. Immunoblot of pSer935LRRK2, total LRRK2, pThr73 Rab10, total Rab10 and loading control α-tubulin from one experiment. b) Equal numbers of MODE-K cells were treated for 24 h with or without MLi-2 (100 nM), and with or without TLR2 and NOD2 agonists Pam3CSK4 (1 µg/ml), MDP (10 µg/mL). Supernatants were collected and used to measure IL-6 by ELISA from 3 independent experiments. Significance was determined by two-way ANOVA and Šídák’s multiple comparisons test. c) Signalling downstream of NOD2/TLR2 was investigated in MODE-K cells treated for 4hrs with or without MLi-2 (100 nM), and with or without TLR2 and NOD2 agonists Pam3CSK4 (1 µg/ml), MDP (10 µg/mL). Immunoblotting for pSer536 p65, total p65, pThr180/Tyr182 p38, total p38 and tubulin as a loading control are shown. d) Quantification of p-p38 normalised to the loading control from 4 independent replicates is shown. Significance was determined by two-way ANOVA and Šídák’s multiple comparisons test. Mean +/- s.d. and individual replicates are represented as bars, error bars and dots, respectively.
Supplementary information
Supplementary Table 1
Processed mass spectrometry proteomics data of small intestinal epithelial cells from C57BL/6J mice
Source data
Source Data Fig. 1
Source data for the graphs in Fig. 1 and Extended Data Figs. 1 and 2.
Source Data Fig. 1
Uncropped immunoblots for each immunoblot in Fig. 1b.
Source Data Extended Data Fig. 1
Uncropped immunoblots for each immunoblot in Extended Data Fig. 1a.
Source Data Extended Data Fig. 2
Uncropped immunoblots for each immunoblot in Extended Data Fig. 2a.
Source Data Extended Data Fig. 2
Uncropped immunoblots for each immunoblot in Extended Data Fig. 2c.
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Tasegian, A., Dikovskaya, D., Scott, M.M. et al. LRRK2 is not required for lysozyme expression in Paneth cells. Nat Immunol 25, 2037–2039 (2024). https://doi.org/10.1038/s41590-024-01972-0
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DOI: https://doi.org/10.1038/s41590-024-01972-0
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