A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells

Cadwell, Ken; Liu, John Y.; Brown, Sarah; Miyoshi, Hiroyuki; Loh, Joy; Lennerz, Jochen K.; Kishi, Chieko; Kc, Wumesh; Carrero, Javier A.; Hunt, Steven R.; Stone, Christian D.; Brunt, Elizabeth M.; Xavier, Ramnik J.; Sleckman, Barry P.; Li, Ellen; Mizushima, Noboru; Stappenbeck, Thaddeus S.; Virgin, Herbert W.

doi:10.1038/nature07416

Cited by 1,357 publications

(1,467 citation statements)

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“…4 Enteral starvation and total parenteral nutrition, as applied to critically ill patients, are reported to result in increased gut wall permeability, a compromised immune system, and bacterial translocation. [5][6][7][8][9][10] Because autophagy, a process induced on starvation, [11][12][13] influences the generation of Paneth cell granules, 14 we hypothesize that enteral starvation impairs Paneth cell function, contributing to starvation-associated gut compromise.…”

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Starvation Compromises Paneth Cells

Hodin

Lenaerts

Grootjans

et al. 2011

The American Journal of Pathology

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The intestine is challenged with the task of protecting the body's internal milieu against bacterial invasion. To this end, the gut is equipped with an epithelial lining connected by tight junctions, a mucus layer, gut-associated lymphoid tissue, and Paneth cells. Paneth cells are highly specialized epithelial cells located in the crypts of the small intestine, and play an important role in gut innate immunity. 1 These cells sense bacterial presence and secrete granules containing antimicrobial peptides, including lysozyme, RegIII␥, and cryptdins (the murine counterparts of human ␣-defensins) both constitutively and in response to activation by bacteria or their products. 2 Using a murine cell ablation model, Paneth cells were shown to be crucial in host protection against invasion of both commensal and pathogenic microbiota. 3 In addition, our group has recently shown the additive importance of Paneth cells in preventing bacterial translocation in situations of physical intestinal barrier loss. 4 Enteral starvation and total parenteral nutrition, as applied to critically ill patients, are reported to result in increased gut wall permeability, a compromised immune system, and bacterial translocation. 5-10 Because autophagy, a process induced on starvation, 11-13 influences the generation of Paneth cell granules, 14 we hypothesize that enteral starvation impairs Paneth cell function, contributing to starvation-associated gut compromise.In this study, the effects of food deprivation on Paneth cell function were investigated using a mouse starvation model. We provide evidence that lack of enteral feeding results in Paneth cell autophagy, decreased expression of antimicrobial products (ie, lysozyme, cryptdin, and RegIII␥), and the presence of atypical secretory granules. Our results propose compromised Paneth cells to be involved in the reduced protection against bacterial translocation in enteral starvation.

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mentioning

confidence: 99%

Starvation Compromises Paneth Cells

Hodin

Lenaerts

Grootjans

et al. 2011

The American Journal of Pathology

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“…ATG16L1 deficient macrophages produce excessive amounts of cytokines after stimulation with LPS [63], partial deficiency of Atg16L1 can lead to reduced production of antimicrobial peptides by Paneth cells in the intestine, impairing antimicrobial immunity which may predispose to intestinal inflammation [64]. The ER-stress signal transducing protein, XBP-1 is critical in regulating the survival of Paneth cells.…”

Section: Protein Misfolding and Proteotoxic Stress In Non-mendelian Imentioning

confidence: 99%

Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond

et al. 2015

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Cells have a number of mechanisms to maintain protein homeostasis, including proteasomemediated degradation of ubiquitinated proteins and autophagy, a regulated process of 'self-eating' where the contents of entire organelles can be recycled for other uses. The unfolded protein response prevents protein overload in the secretory pathway. In the past decade, it has become clear that these fundamental cellular processes also help contain inflammation though degrading pro-inflammatory protein complexes such as the NLRP3 inflammasome. Signaling pathways such as the UPR can also be co-opted by tolllike receptor and mitochondrial reactive oxygen species signaling to induce inflammatory responses.Mutations that alter key inflammatory proteins, such as NLRP3 or TNFR1, can overcome normal protein homeostasis mechanisms, resulting in autoinflammatory diseases. Conversely, Mendelian defects in the proteasome cause protein accumulation, which can trigger interferon-dependent autoinflammatory disease. In non-Mendelian inflammatory diseases, polymorphisms in genes affecting the UPR or autophagy pathways can contribute to disease, and in diseases not formerly considered inflammatory such as neurodegenerative conditions and type 2 diabetes, there is increasing evidence that cell intrinsic or environmental alterations in protein homeostasis may contribute to pathogenesis.3 Cells must maintain a delicate balance between the demands for protein synthesis and the need to avoid accumulation of incompletely processed or unfolded proteins that can accumulate under normal conditions and even more so when cells face a variety of stresses. The unfolded protein response (UPR) is an evolutionarily conserved mechanism to maintain cellular homeostasis by preventing the accumulation of misfolded proteins in the endoplasmic reticulum (ER). Disturbed protein folding in the ER is primarily detected by three transmembrane (TM) proteins: activating transcription factor 6 (ATF6), inositol-requiring transmembrane kinase/endonuclease 1 (IRE1) and pancreatic ER kinase (PERK). The combined action of these sensors reduces global protein synthesis while upregulating the production of chaperone proteins that can stabilize misfolded proteins. Apart from ER homeostasis, the UPR can modulate other biological functions, including apoptosis, protein secretion, and as we will discuss further, inflammatory responses [1,2].A series of molecular changes are initiated in response to cellular stressors in order to minimize damage caused by unfavorable environmental conditions, such as temperature changes, toxins (e.g. bacterial, chemical), radiation, mechanical damage, nutritional status as well as incompletely folded proteins intracellularly (Figure 1). The UPR serves the adaptive purpose of protecting the cell by activating a series of mechanisms including the induction of molecular chaperones to assist with correct folding -e.g. heat shock proteins and foldases. Interestingly there are a number of connections between the UPR and inflammatory signaling pat...

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“…Des anomalies de fonction des cellules de Paneth ont été rapportées chez des patients atteints de MC et homozygotes pour l'allèle T300A du gène Atg16L1 impliqué dans l'autophagie [33]. De plus, des études récentes ont démontré que certains variants du gène codant pour le facteur de transcription TCF4, impliqué dans la maturation et la fonction des cellules de Paneth, sont associés à la MC iléale.…”

Section: Peptides Antimicrobiens Et Miciunclassified