How autophagy controls the intestinal epithelial barrier.

ABSTRACT

Macroautophagy/autophagy is a cellular catabolic process that results in lysosome-mediated recycling of organelles and protein aggregates, as well as the destruction of intracellular pathogens. Its role in the maintenance of the intestinal epithelium is of particular interest, as several autophagy-related genes have been associated with intestinal disease. Autophagy and its regulatory mechanisms are involved in both homeostasis and repair of the intestine, supporting intestinal barrier function in response to cellular stress through tight junction regulation and protection from cell death. Furthermore, a clear role has emerged for autophagy not only in secretory cells but also in intestinal stem cells, where it affects their metabolism, as well as their proliferative and regenerative capacity. Here, we review the physiological role of autophagy in the context of intestinal epithelial maintenance and how genetic mutations affecting autophagy contribute to the development of intestinal disease.Abbreviations AKT1S1 AKT1 substrate 1; AMBRA1 autophagy and beclin 1 regulator 1; AMPK AMP-activated protein kinase; APC APC regulator of WNT signaling pathway; ATF6 activating transcription factor 6; ATG autophagy related; atg16l1[ΔIEC] mice mice with a specific deletion of Atg16l1 in intestinal epithelial cells; ATP adenosine triphosphate; BECN1 beclin 1; bsk/Jnk basket; CADPR cyclic ADP ribose; CALCOCO2 calcium binding and coiled-coil domain 2; CASP3 caspase 3; CD Crohn disease; CDH1/E-cadherin cadherin 1; CF cystic fibrosis; CFTR CF transmembrane conductance regulator; CGAS cyclic GMP-AMP synthase; CLDN2 claudin 2; CoPEC colibactin-producing E. coli; CRC colorectal cancer; CYP1A1 cytochrome P450 family 1 subfamily A member 1; DC dendritic cell; DDIT3 DNA damage inducible transcript 3; DEPTOR DEP domain containing MTOR interacting protein; DSS dextran sulfate sodium; EGF epidermal growth factor; EGFR epidermal growth factor receptor; EIF2A eukaryotic translation initiation factor 2A; EIF2AK3 eukaryotic translation initiation factor 2 alpha kinase 3; EIF2AK4/GCN2 eukaryotic translation initiation factor 2 alpha kinase 4; ER endoplasmic reticulum; ERN1 endoplasmic reticulum to nucleus signaling 1; GABARAP GABA type A receptor-associated protein; HMGB1 high mobility group box 1; HSPA5/GRP78 heat shock protein family A (Hsp70) member 5; IBD inflammatory bowel disease; IEC intestinal epithelial cell; IFN interferon; IFNG/IFNγinterferon gamma; IL interleukin; IRGM immunity related GTPase M; ISC intestinal stem cell; LGR5 leucine rich repeat containing G protein-coupled receptor 5; LRRK2 leucine rich repeat kinase 2; MAP1LC3A/LC3 microtubule associated protein 1 light chain 3 alpha; MAPK/JNK mitogen-activated protein kinase; MAPK14/p38 MAPK mitogen-activated protein kinase 14; MAPKAP1 MAPK associated protein 1; MAVS mitochondrial antiviral signaling protein; miRNA microRNA; MLKL mixed lineage kinase domain like pseudokinase; MLST8 MTOR associated protein, LST8 homolog; MNV murine norovirus; MTOR mechanistic target of rapamycin kinase; NBR1 NBR1 autophagy cargo receptor; NLRP NLR family pyrin domain containing; NOD nucleotide binding oligomerization domain containing; NRBF2 nuclear receptor binding factor 2; OPTN optineurin; OXPHOS oxidative phosphorylation; P phosphorylation; Patj PATJ crumbs cell polarity complex component; PE phosphatidyl-ethanolamine; PI3K phosphoinositide 3-kinase; PIK3C3/VPS34 phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3R4 phosphoinositide-3-kinase regulatory subunit 4; PPARG peroxisome proliferator activated receptor gamma; PRR5 proline rich 5; PRR5L proline rich 5 like; PtdIns3K phosphatidylinositol 3-kinase; PtdIns3P phosphatidylinositol 3-phosphate; RB1CC1/FIP200 RB1 inducible coiled-coil 1; RER rough endoplasmic reticulum; RHEB Ras homolog, MTORC1 binding; RICTOR RPTOR independent companion of MTOR complex 2; RIPK1 receptor interacting serine/threonine kinase 1; ROS reactive oxygen species; RPTOR regulatory associated protein of MTOR complex 1; RPS6KB1 ribosomal protein S6 kinase B1; SH3GLB1 SH3 domain containing GRB2 like, endophilin B1; SNP single-nucleotide polymorphism; SQSTM1 sequestosome 1; STAT3 signal transducer and activator of transcription 3; STING1 stimulator of interferon response cGAMP interactor 1; TA transit-amplifying; TFEB transcription factor EB; TFE3 transcription factor binding to IGHM enhancer 3; TGM2 transglutaminase 2; TJ tight junction; TJP1/ZO1 tight junction protein 1; TNBS 2,4,6-trinitrobenzene sulfonic acid; TNF/TNFα tumor necrosis factor; Tor target of rapamycin; TRAF TNF receptor associated factor; TRIM11 tripartite motif containing 11; TRP53 transformation related protein 53; TSC TSC complex subunit; Ub ubiquitin; UC ulcerative colitis; ULK1 unc-51 like autophagy activating kinase 1; USO1/p115 USO1 vesicle transport factor; UVRAG UV radiation resistance associated; WIPI WD repeat domain, phosphoinositide interacting; WNT WNT family member; XBP1 X-box binding protein 1; ZFYVE1/DFCP1 zinc finger FYVE-type containing 1.