PXD010940

PXD010940 is an original dataset announced via ProteomeXchange.

Title	Integrative analysis of Paneth cell proteomic data from intestinal organoids reveals functional processes affected in Crohn’s disease due to autophagy impairment
Description	Crohn’s disease (CD) is associated with multiple Paneth cell dysfunctions such as altered antimicrobial secretion that relies on autophagy - an essential process controlling the turnover of cellular components. Genome-wide association studies have linked CD to mutations in the ATG16l1 gene, encoding an important component of the autophagy machinery. Patients carrying the ATG16l1 CD risk allele have Paneth cell abnormalities, as reproduced in Atg16l1-deficient mouse models. However, the direct effect of the ATG16L1-deficiency and autophagy-impairment in Paneth cells has not been analysed in detail. To investigate this, we generated a mouse model lacking ATG16L1 specifically in intestinal epithelial cells (Atg16l1△IEC) making these cells impaired in autophagy. Using a 3D small intestinal organoid culture model, which we enriched for Paneth cells and compared the proteomic profiles of organoids derived from the wild-type (WT) and the Atg16l1△IEC mice. We used an integrated computational approach combining protein-protein interaction networks, list of proteins potentially targeted by autophagy and functional information on the proteins with altered protein levels to identify the mechanistic link between autophagy-impairment and disrupted cellular process. 198 (70%) of the 284 altered proteins were more abundant in autophagy-impaired organoids than WT organoids that could be due to a reduced protein turnover. Combining the proteomic dataset with the potential target proteins of selective autophagy proteins revealed that 116 (41%) of the differentially abundant proteins could rely on autophagy-mediated turnover. Taken together, our results suggest that proteins with increased levels in autophagy-impaired background require an autophagy-mediated turnover mechanism, and that their altered levels in CD could affect key cellular processes. Consequently, we pointed out the importance of autophagy in controlling the turnover of proteins relevant in key Paneth cell functions such as exocytosis, apoptosis and DNA damage repair. Our study unravels autophagy-dependent cellular processes of Paneth cells that not directly relies on the autophagy process, rather than a selective protein turnover mechanism. The identified proteins and processes open new avenues for targeted, cell type-specific therapeutic interventions in CD.
HostingRepository	PRIDE
AnnounceDate	2019-03-07
AnnouncementXML	Submission_2019-04-03_07:23:06.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD010940
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Stuart Armstrong
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue; deamidated residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2018-08-30 01:43:46	ID requested
1	2019-03-07 07:44:18	announced
⏵ 2	2019-04-03 07:23:07	announced	Updated publication reference for PubMed record(s): 30814064.

Jones EJ, Matthews ZJ, Gul L, Sudhakar P, Treveil A, Divekar D, Buck J, Wrzesinski T, Jefferson M, Armstrong SD, Hall LJ, Watson AJM, Carding SR, Haerty W, Di Palma F, Mayer U, Powell PP, Hautefort I, Wileman T, Korcsmaros T, Integrative analysis of Paneth cell proteomic and transcriptomic data from intestinal organoids reveals functional processes dependent on autophagy. Dis Model Mech, 12(3):(2019) [pubmed]

curator keyword: Biomedical

submitter keyword: Paneth cells

ATG16L1

intestinal organoids, quantitative proteomics

selective autophagy

Crohn’s disease

Julian Hiscox
contact affiliation	Chair in Infection and Global Health, Department of Infection Biology, Institute of Infection and Global Health, University of Liverpool, UK
contact email	julianh@liverpool.ac.uk
lab head
Stuart Armstrong
contact affiliation	Infection Biology
contact email	sarmstro@liv.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD010940
     1. Label: PRIDE project
     2. Name: Integrative analysis of Paneth cell proteomic data from intestinal organoids reveals functional processes affected in Crohn’s disease due to autophagy impairment