Wilson, R and Gundamaraju, R and Vemuri, R and Angelucci, C and Geraghty, D and Guven, N and Eri, RD, Identification of key pro-survival proteins in isolated colonic goblet cells of Winnie, a murine model of spontaneous colitis, Inflammatory Bowel Diseases, 26, (1) pp. 80-92. ISSN 1536-4844 (2019) [Refereed Article]
© 2019 Crohn’s & Colitis Foundation. Published by Oxford University Press.
Accumulating evidence suggests that the goblet cell-derived mucin-2 (Muc2) is a major component of the immune system and that perturbations in Muc2 lead to an ulcerative colitis–like phenotype. The animal model Winnie carries a missense mutation in Muc2 that causes Muc2 misfolding, accumulation in goblet cells, and ER stress. Excessive ER stress is a hallmark of many diseases, including ulcerative colitis, cancer, diabetes and Parkinson’s disease. However, rather than committing to cell death, which is the typical outcome of unresolved ER stress, Winnie goblet cells are characterized by hyperproliferation, suggesting additional regulation of this cellular stress response.
To elucidate the molecular mechanisms underlying ulcerative colitis in the Winnie model, we isolated goblet cells from Winnie and wild-type mice and used label-free quantitative proteomics and bioinformatics to understand the functional consequences of Muc2 misfolding and accumulation.
A large number of changes were identified that highlight a dramatic reprogramming of energy production, including enhanced utilization of butyrate, a key energy source of colonic cells. A major finding was the marked upregulation of the coiled-coil-helix-coiled-coil-helix domain proteins Chchd2, Chchd3, and Chchd6. In particular, we identified and confirmed the upregulation and nuclear translocation of Chchd2, a protein known to inhibit oxidative stress induced apoptosis.
This study is the first to apply proteome-level analysis to the preclinical Winnie model of ulcerative colitis. Identification of proteins and pathways affected in isolated Winnie goblet cells provides evidence for novel adaptive mechanisms underlying cell survival under conditions of chronic ER stress.
|Item Type:||Refereed Article|
|Keywords:||ER stress, ulcerative colitis, proteomics, apoptosis, profileration|
|Research Division:||Biomedical and Clinical Sciences|
|Research Group:||Clinical sciences|
|Research Field:||Gastroenterology and hepatology|
|Objective Group:||Clinical health|
|Objective Field:||Clinical health not elsewhere classified|
|UTAS Author:||Wilson, R (Dr Richard Wilson)|
|UTAS Author:||Gundamaraju, R (Mr Rohit Gundamaraju)|
|UTAS Author:||Vemuri, R (Mr Ravichandra Vemuri)|
|UTAS Author:||Angelucci, C (Dr Constanza Angelucci)|
|UTAS Author:||Geraghty, D (Professor Dominic Geraghty)|
|UTAS Author:||Guven, N (Dr Nuri Guven)|
|UTAS Author:||Eri, RD (Associate Professor Raj Eri)|
|Web of Science® Times Cited:||23|
|Deposited By:||Central Science Laboratory|
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