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Keratin Intermediate Filaments as Regulators of Epithelial Intracellular Organization Keratin intermediate filaments are cytoskeletal proteins regulating the polarity and intracellular organization

Final Report Summary - KIFREIO (Keratin Intermediate Filaments as Regulators of Epithelial Intracellular Organization Keratin intermediate filaments are cytoskeletal proteins regulating the polarity a

Project context and objectives

Keratin intermediate filaments (IFs) help protect tissues and cells from stress, but mutations in keratins lead to multiple human diseases. The major keratin (K) in intestinal epithelia is K8 and its mouse knock-out leads to colonic hyperproliferation and inflammation, similar to the human disease ulcerative colitis. The K8-null phenotype is accompanied by altered ion transport, mistargetting of membrane transporters and diarrhoea. The molecular roles for keratins in the intestine are still, however, largely unknown and are the focus of these studies. The overall objectives were to study how epithelial and, in particular, intestinal keratin IFs help protect from stress and maintain health, and to utilise the K8-null mouse to model central questions on colitis in general. The specific aims of these studies were to investigate the roles of keratin in energy metabolism, differentiation and cell proliferation.

Work performed

In these studies, we have disseminated that the colonic ketogenic mitochondrial HMG-CoA synthase (HMGCS2) is an important pathway for keratins to protect the colon from stress. In the K8KO colon, the ketogenic pathway is blunted by ketogenic stimuli, such as starvation or a ketogenic diet. Keratins appear to regulate these and other related processes by targeting proteins to their correct place in the cell. Energy levels affect balances in proliferation, cell death and differentiation in the intestinal epithelium, and we have observed changes in the K8-null colon, such as increased proliferation and decreased apoptosis, which is reversed after treatment with antibiotics. This relates intimately to the interaction of the epithelium with enteric bacteria and the short chain fatty acid energy source they produce. Regulation of proliferation and cell death is also important for the development of cancer and we have observed increased susceptibility to colorectal cancer related to keratin-status. K8 heterozyous mice express 50 % less keratins than wild-type (WT), have a mild colonic-non inflammatory-phenotype, and are more sensitive to experimental colitis. This also makes the K8 heterozyous mouse an attractive model in which to study the very mechanisms of keratins in the absence of inflammation, and we have utilised this model to develop novel simple and cost-effective in vivo imaging techniques for experimental murine colitis.

Main results

Together these findings support the hypothesis that keratins modulate ketone body and energy metabolism in colonic epithelia, which in turn regulates apoptosis, cell proliferation and intracellular ion-homeostasis, as well as a susceptibility to colon cancer. Current studies aim to further unravel the mechanisms of keratins in intestinal epithelia in health and disease. These studies will shed light on the molecular mechanism of keratins, which should help understand human intestinal health and disease like inflammatory bowel disease and colon cancer.