How autophagy controls the intestinal epithelial barrier

Figures & data

Table 1. Genetic models deciphering the role of autophagy in the intestinal epithelium

Genetic Background (species)	Physiological Condition(s)/ Injury Model(s)	Altered Signaling Pathway(s)/ Major Intestinal Phenotype(s)	Reference(s)
ATG16L1^T300A (Homo sapiens)	CD patients	heightened ER stress in Paneth cells	Deuring et al., 2014 [86]
	CRC patients	better life expectancy, increased type I IFN	Grimm et al., 2016 [157]
		increased risk of CRC	Nicoli et al., 2014 [158]
XBP1 hypomorphic polymorphism (Homo sapiens)	CD patients	loss of Paneth cells, reduced antimicrobial peptide secretion	Kaser et al., 2008 [78]
atg14[ΔIEC] (Mus musculus)	Homeostasis	TNF-dependent spontaneous villus atrophy and intestinal enterocytes	Jung et al., 2019 [105]
atg16l1[ΔIEC] (Mus musculus)	Homeostasis	heightened ER stress, spontaneous development of CD-like ileitis in aged mice, defective Paneth cells	Adolph et al., 2013 [69]; Tschurtschenthaler et al., 2017 [65]
	MNV infection followed by DSS-induced colitis	exaggerated intestinal cell death, TNF-mediated intestinal necroptosis, reduced Paneth cell numbers and other secretory cell-types	Matsuzawa-Ishimoto et al., 2017 [98]
	Helicobacter hepaticus infection coupled with IL10 blockade	excessive proinflammatory cytokine release, exacerbated tissue pathology, increased TNF-induced IEC apoptosis	Pott et al., 2018 [100]
	Citrobacter rodentium infection	no difference from wild type	Pott et al., 2018 [100]
		decreased infectious burden	Martin et al., 2018 [133]
	IL22 injection	TNF signaling-mediated CGAS-STING1 triggered RIPK3-MLKL axis dependent IEC necroptosis	Aden et al., 2019 [103]
	Radiation-induced injury	defective mitophagy, increased ROS in ISCs, impaired ISC regeneration, metabolic dysregulation	Levy et al., 2020 [77]
atg16l1[ΔIEC]; apc^Min/+	apc^Min/+ model of CRC with CoPEC infection	increased DNA damage, inflammation, and carcinogenesis	Lucas et al., 2020 [159]
atg16l1^fl/fl Defa4/αDefensin4 IRES-cre (Mus musculus)	Cigarette smoke model	enhanced TNF-mediated crypt base and Paneth cell apoptosis	Liu et al., 2018 [164]
atg16l1;xbp1[ΔIEC] (Mus musculus)	Homeostasis	increased NFKB and TNF signaling, exacerbated transmural inflammation	Adolph et al., 2013 [69]
	Homeostasis	develop early life transmural ileitis	Tschurtschenthaler et al., 2017 [65]
atg16l1^HM (Mus musculus)	Homeostasis	dysmorphic Paneth cells, decreased lysozyme secretion	Cadwell et al., 2008 [63]; Cadwell et al., 2009 [70]
		increased type I IFN	Marchiando et al., 2013 [132]; Martin et al., 2018 [133]
	MNV infection followed by DSS-induced acute colitis	TNF and IFNG/IFN-γ-mediated intestinal inflammation, proximal epithelial hyperplasia	Cadwell et al., 2010 [68]
	Citrobacter rodentium infection	decreased infectious burden	Marchiando et al., 2013 [132]; Martin et al., 2018 [133]
atg16l1^T316A (Mus musculus)	Homeostasis	defective Paneth cell and goblet cell morphology	Lassen et al., 2014 [74]
	Salmonella Typhimurium infection	decreased lysozyme secretion	Bel et al., 2017 [137]
	Citrobacter rodentium infection with Pac-1 treatment	decreased infectious burden	Martin et al., 2018 [133]
	Cigarette smoke model	metabolic dysregulation, enhanced crypt base apoptosis, defective Paneth cell morphology	Liu et al., 2018 [164]
atg4b^−/- (Mus musculus)	DSS-induced acute colitis	increased proinflammatory cytokines, abnormal Paneth cells	Cabrera et al., 2013 [136]
	Citrobacter rodentium infection	decreased infectious burden	Martin et al., 2018 [133]
atg5[ΔIEC] (Mus musculus)	Shigella infection model	enhanced crypt cell death, increased epithelial shedding, ileal inflammation	Chang et al., 2013 [165]
	Salmonella Typhimurium infection	increased burden of infection	Benjamin et al., 2013 [66]
	Radiation-induced injury	defective mitophagy, increased ROS in ISCs, impaired ISCs regeneration	Asano et al., 2017 [76]
	Homeostasis	defective Paneth cells	Burger et al., 2018 [99]
	Toxoplasma gondii infection model	cytokine-mediated Paneth cell loss, TNF- and IFNG-driven intestinal cell death, reduced antimicrobial peptide expression
atg5^fl/fl Defa4 IRES-cre (Mus musculus)	Toxoplasma gondii infection model	Paneth cell loss	Burger et al., 2018 [99]
atg5^+/-;apc^Min/+ (Mus musculus)	apc^Min/+ model of CRC	increased tumor burden, better response to treatment with IFNG	Wang et al., 2015 [160]
atg7[ΔIEC] (Mus musculus)	Homeostasis	defective Paneth cells	Wittkopf et al., 2012 [64]
	DSS-induced acute colitis	no difference from wild type
	Citrobacter rodentium infection	no difference from wild type
	Shigella infection model	increased pathology, increased infectious burden	Inoue et al., 2012 [166]
	Listeria monocytogenes infection	enhanced crypt cell death, increased epithelium shedding, ileal inflammation	Chang et al., 2013 [165]
		increased infectious burden	Sorbara et al., 2018 [58]
atg7^fl/fl Vil1-CreERT2 (Mus musculus)	Tamoxifen-induced IEC -specific deletion model	increased mitochondria defects, DNA damage, and ROS, more TRP53-mediated ISC apoptosis, defective crypt regeneration	Trentesaux et al., 2020 [106]
atg7[ΔIEC];apc^Min/+	apc^Min/+ model of CRC	decreased tumor burden, increased anti-tumor immune response	Lévy et al., 2015 [140]
atg7;xbp1[ΔIEC] (Mus musculus)	Homeostasis	increased NFKB/NFκB and TNF signaling, exacerbated transmural inflammation	Adolph et al., 2013 [69]
chuk^AA/AA (Mus musculus)	DSS-induced acute colitis	heightened ER stress, less autophagy, defective Paneth cell morphology and goblet cell function	Diamanti et al., 2017 [167]
eif2ak4[ΔIEC] (Mus musculus)	Starvation-induced intestinal dysfunction	impaired autophagy, increased ROS, enhanced NLRP3 inflammasome-mediated IL1B production, increased Th17 response	Ravindran et al., 2016 [79]
hmgb1[ΔIEC] (Mus musculus)	DSS-induced acute colitis	increased IEC apoptosis	Zhu et al., 2015 [101]
irgm1^−/- (Mus musculus)	Homeostasis	impaired autophagy and mitophagy, abnormal Paneth cells, reduced antimicrobial peptides	Liu et al., 2013 [71]
	DSS-induced acute colitis	increased focal epithelial denudation, mild goblet cell depletion,	Liu et al., 2013 [71]
		defective Paneth cell function, mild crypt epithelial cell hyperplasia	Rogala et al., 2018 [72]
lrrk2^−/- (Mus musculus)	Homeostasis	defective lysosomal sorting, impaired Paneth cell autophagy	Zhang et al., 2015 [73]
map1lc3b^−/-	Citrobacter rodentium infection	decreased infectious burden	Martin et al., 2018 [133]
mtor[ΔIEC] (Mus musculus)	Homeostasis	no MTOR signaling, increased enteroendocrine cells, defective Paneth cells and goblet cells, villus blunting	Sampson et al., 2016 [118]
	Radiation-induced injury	impaired regeneration due to decreased ISC proliferation
nlrp6^−/- (Mus musculus)	Homeostasis	impaired autophagy, defective goblet cell function and mucus secretion	Wlodarska et al., 2014 [92]
rb1cc1/fip200[ΔIEC] (Mus musculus)	Homeostasis	TNF-dependent spontaneous villus atrophy and intestinal enterocyte loss	Jung et al., 2019 [105]
rictor[ΔIEC] (Mus musculus)	Homeostasis	no MTORC2 signaling, larger goblet cell size	Sampson et al., 2016 [118]
rptor[ΔIEC] (Mus musculus)	Homeostasis	no MTORC1 signaling, moderate ileal villus blunting, loss of Paneth cells increased enteroendocrine numbers	Sampson et al., 2016 [118]; Barron et al., 2017 [168]
rptor;rictor[ΔIEC] (Mus musculus)	Homeostasis	no MTOR signaling, severe villus flattening, decreased goblet cell size	Sampson et al., 2016 [118]
tfeb[ΔIEC] (Mus musculus)	Homeostasis	defective Paneth cells	Murano et al., 2017 [120]
	DSS-induced acute colitis	worsened pathology, barrier permeability
tsc1[ΔIEC] (Mus musculus)	Small bowel resection (SBR)	enhanced MTOR signaling, robust villus growth, stronger crypt cell proliferation	Barron et al., 2017 [168]
	Homeostasis	enhanced MTOR signaling, increased crypt numbers and size	He et al., 2020 [128]
tsc1^fl/fl Lgr5-CreERT (Mus musculus)	Tamoxifen-induced ISC-specific deletion model	enhanced MTOR-mediated MAPK14-TRP53 signaling, ISC/TA hyperproliferation	He et al., 2020 [128]
xbp1[ΔIEC] (Mus musculus)	Homeostasis	increased autophagy, loss of Paneth cell and goblet cells, reduced antimicrobial peptide secretion, susceptible to Listeria monocytogenes infection, epithelial hyperproliferation, increased ISC numbers, enhanced TA proliferation	Kaser et al., 2008 [78]; Niederreiter et al., 2013 [83]; Adolph et al., 2013 [69]; Tschurtschenthaler et al., 2017 [65]
	DSS-induced acute colitis	increased TNF signaling, intestinal edema, erosion and crypt loss	Kaser et al., 2008 [78]
hmgb1[ΔIEC] (Rattus norvegicus)	Acute necrotizing pancreatitis model	excessive autophagy, increased degradation of TJP1/ZO-1, CLDN2 and OCLN in the intestine	Huang et al., 2019 [169]
Atg1 deletion mutant (Drosophila melanogaster)	Homeostasis	increased Tor activity, aberrant enlargement of IECs	Wen et al., 2017 [111]
Atg2, Atg3, Atg18 RNAi esg-specific expression (Drosophila melanogaster)	Homeostasis and upon DSS treatment	defective mitosis, decreased ISC numbers in midgut	Nagy et al., 2018 [123]
Atg6 ISC- and enteroblast-specific deletion mutant (Drosophila melanogaster)	Homeostasis	centrosome amplification and DNA damage accumulation, ISC hyperproliferation, intestinal hyperplasia	Na et al., 2018 [122]
Atg8a deletion mutant (Drosophila melanogaster)	Homeostasis	altered morphology ISCs, decreased ISC proliferation and regeneration	Nagy et al., 2018 [123]
Atg9 deletion mutant (Drosophila melanogaster)	Homeostasis	increased ROS activity, inhibition of bsk/Jnk signaling, impaired ISC proliferation	Tang et al., 2013 [87]
		increased Tor activity, aberrant enlargement of IECs	Wen et al., 2017 [111]
Atg13 deletion mutant (Drosophila melanogaster)	Homeostasis	increased Tor activity, aberrant enlargement of IECs	Wen et al., 2017 [111]
Atg14 RNAi esg-specific expression (Drosophila melanogaster)	Homeostasis and upon DSS treatment	defective mitosis, decreased ISC numbers in midgut	Nagy et al., 2018 [123]
Atg17/Fip200 deletion mutant (Drosophila melanogaster)	Homeostasis	increased Tor activity, aberrant enlargement of IECs	Wen et al., 2017 [111]
Atg101^6h loss-of-function mutant (Drosophila melanogaster)	Homeostasis	shorter and thicker midguts, abnormal morphology with enlarged enterocytes, ISC hyperproliferation	Guo et al., 2019 [124]

Figure 1. Overview of autophagy and autophagic regulation. In mammals, autophagy is initiated by the ULK1 complex [27], which, along with the PtdIns3K complex [28,29] participates in assembling the autophagic machinery on the rough ER. Additional complexes, such as the ATG12 conjugation system, assemble on the forming phagophore to which autophagic targets are recruited [31]. Targets can be labeled by ubiquitin chains, as well as cargo receptors, including SQSTM1, and CALCOCO2 [24]. After lysosomal fusion, the contents of the autolysosome are degraded, and nutrients are recycled by the cell [24]. The initiation of autophagy is tightly regulated by multiple members of the MTOR pathway, including AMPK [42], MTORC1 [42,43], TFEB and TFE3 [46-48]. AMBRA1: autophagy and beclin 1 regulator 1; NRBF2: nuclear receptor binding factor 2; P: phosphorylation; PE: phosphatidylethanolamine; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3R4: phosphoinositide-3-kinase regulatory subunit 4; RER: rough endoplasmic reticulum; Ub: ubiquitin; USO1/p115: USO1 vesicle transport factor; ZFYVE1/DFCP1: zinc finger FYVE-type containing 1.

Figure 2. Intestinal epithelial cell-specific effects due to autophagy deficiency and intestinal injury. The autophagy–deficient intestinal epithelium is more susceptible to injury [76,98-100]. IECs require autophagy to protect from TNF- and IFNG–induced cell death [98-100], which is proposed to occur through RIPK3-MLKL-mediated necroptosis [98]. It has also been shown to specifically affect Paneth cells resulting in decreased antimicrobial peptides [99]. Autophagy-deficiency in ISCs results in increased ROS from mitochondrial defects, which leads to increased cell death [77] and reduced regeneration in response to irradiation [76]. Autophagy in goblet cells is required for ROS-mediated mucin secretion at baseline [91].

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