9/20/2023 0 Comments Incontrol sc2 dead![]() Here we report that peroxisomes in the Drosophila gut modulate target of rapamycin (Tor) kinase-dependent autophagy, stress signaling and tissue regeneration to maintain gut epithelium homeostasis, promote gut epithelium renewal, and ultimately influence host–commensal and host–pathogen interactions needed for the survival and development of Drosophila.ĭysfunctional peroxisomes lead to increased lysosomal and autophagic activity in the gut epithelium Therefore, stress response programs and increased epithelial renewal need to be activated to repair the intestinal epithelium when damaged and thereby maintain the integrity of the gut barrier. Differentiated cells in the Drosophila gut epithelium undergo normal turnover, but turnover is more rapid in damaged tissue ( Amcheslavsky et al., 2009 Buchon et al., 2009). Studies of the Drosophila gut have been at the forefront of recent research on host–commensal and host–pathogen interactions, innate immune signaling, and the regenerative capacity of the intestinal epithelia ( Buchon et al., 2013 Lemaitre and Miguel-Aliaga, 2013). Because peroxisomes are notably abundant in gut epithelial cells ( Novikoff and Novikoff, 1972 Beard and Holtzman, 1987 Faust et al., 2014 Morvay et al., 2017) and because gastrointestinal bleeding has been reported in PBD patients ( Lodhi and Semenkovich, 2014), we investigated a potential requirement for peroxisomes in maintaining the structure and function of the gut epithelium using Drosophila as a model. Emerging evidence suggests that peroxisomes are pivotal to the development and survival of different tissues for example, peroxisomes are recognized mediators of brain development ( Berger et al., 2016) and of skeletal muscle formation and integrity ( Braverman et al., 2013). Peroxisome deficiency or functional impairments directly due to defective peroxisome formation result in devastating genetic conditions known as the peroxisome biogenesis disorders (PBDs) ( Waterham et al., 2016) contribute to the pathology of Alzheimer’s and Parkinson’s diseases, aging, cancer, diabetes, and heart failure and affect immunity ( Dixit et al., 2010 Beach et al., 2012 Fransen et al., 2012 Colasante et al., 2015 Di Cara et al., 2017). Peroxisomes perform many important metabolic functions and maintain cellular redox homeostasis ( Wanders and Waterham, 2006 Nguyen et al., 2008). Peroxin ( Pex) genes encode proteins called peroxins that are required for peroxisome formation and maintenance of peroxisome populations ( Smith and Aitchison, 2013). Peroxisomes are ubiquitous organelles conserved across the breadth of eukaryotes. Understanding how enteric health is maintained therefore has important implications for overall human health and requires knowledge of the signaling pathways that control gut metabolism, stress response, and interactions with microbes. The intestinal epithelium absorbs nutrients, maintains energy homeostasis, and manages interactions with microorganisms to provide resistance to pathogens and to promote beneficial contacts with commensals ( Clemente et al., 2012 Hooper et al., 2012 Nicholson et al., 2012 Lemaitre and Miguel-Aliaga, 2013 Guo et al., 2014). Peroxisomes in the gut effectively function as hubs that coordinate responses from stress, metabolic, and immune signaling pathways to maintain enteric health and the functionality of the gut–microbe interface. Dysfunctional peroxisomes in gut epithelial cells activate Tor kinase-dependent autophagy that increases cell death and epithelial instability, which ultimately alter the composition of the intestinal microbiota, compromise immune pathways in the gut in response to infection, and affect organismal survival. We report that peroxisomes, organelles involved in lipid metabolism and redox balance, are required to maintain gut epithelium homeostasis and renewal in Drosophila and for survival and development of the organism. Gut homeostasis is necessary for organismal health and changes to the gut are associated with conditions like obesity and diabetes and inflammatory illnesses like Crohn’s disease. The gut has a central role in digestion and nutrient absorption, but it also serves in defending against pathogens, engages in mutually beneficial interactions with commensals, and is a major source of endocrine signals.
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