Autophagy as a Gatekeeper of Intestinal Homeostasis

The control of gut homeostasis by autophagy in the context host-microbiota relationship remains poorly understood. In this issue Developmental Cell, Nagai et al., 2021Nagai H. Tatara Tanaka-Furuhashi K. Kurata S. Yano T. Homeostatic regulation ROS-triggered Hippo-Yki pathway via autophagic clearance Ref(2)P/p62 Drosophila intestine.Dev. Cell. 2021; 56 (this issue): 81-94Abstract Full Text PDF Scopus (4) Google Scholar show that plays a crucial role enterocytes to prevent mis-regulation Hippo-Yorkie microbiota. addition its function digestion, intestinal epithelium has defining barrier between host and external environment. This protects against invasion systemic dissemination both pathogenic commensal microorganisms. Damage must be quickly repaired penetration bacteria. is possible due gut’s dynamic nature involves epithelial renewal appropriate immune response. Homeostasis, therefore, requires balance response tolerance microbes gut. Ruptures are associated humans with development inflammatory bowel disease, such as Crohn’s disease (Torres 2017Torres J. Mehandru Colombel J.-F. Peyrin-Biroulet L. disease.Lancet. 2017; 389: 1741-1755Abstract PubMed (654) Scholar). However, etiology these diseases complex, it challenging delineate causative chain events microbial factors lead progression. largely because underlying not yet fully recent years, emerged powerful model study context, fruit fly been useful better understand defense, contribution aging, and, more globally, integration whole-organism physiology providing sensitive organ assay pathways cellular processes physiological (Lemaitre Miguel-Aliaga, 2013Lemaitre B. Miguel-Aliaga I. digestive tract melanogaster.Annu. Rev. Genet. 2013; 47: 377-404Crossref (247) Macroautophagy (hereafter autophagy) an important process removes damaged organelles or protein complexes through formation autophagosomes (Dikic Elazar, 2018Dikic Elazar Z. Mechanism medical implications mammalian autophagy.Nat. Mol. Cell Biol. 2018; 19: 349-364Crossref (877) Defects autophagy-related genes ATG16L1 IRGM have identified significant risk for Studies shown required stem cells sustain proliferation preserve cell pool (Nagy 2018Nagy P. Sándor G.O. Juhász G. Autophagy maintains Drosophila.Sci. Rep. 8: 4644Crossref (28) also tissue reactive oxygen species (ROS) downstream Jun N-terminal kinase (JNK) (Wu 2009Wu Wang M.C. Bohmann D. JNK from oxidative stress trancriptionally activating autophagy.Mech. Dev. 2009; 126: 624-637Crossref (91) identify preventing activation Hippo presence first investigated enterocytes, main absorptive midgut. To end, they knocked down series genes, including atg7, using RNAi. Even absence challenge, atg7-deficient flies appears disorganized, displaying dysplasia higher rate mislocalization septate junction proteins. Increased intestine can triggered JAK-STAT progenitors ligand Upd3. found relies on Upd3 expression, knocking upd3 atg7-RNAi abrogated mislocalization. Given results, how defective turn expression activate proliferation? metazoans, integrates many signals size regulating apoptosis. Inactivation leads transcription factor Yorkie (Houtz 2017Houtz Bonfini A. Liu X. Revah Guillou Poidevin M. Hens Huang H.-Y. Deplancke Tsai Y.-C. Buchon N. Hippo, TGF-β, Src-MAPK regulate cytokine upon bacterial infection.PLoS 13: e1007091Crossref (31) Scholar, hypothesized overexpression could result inactivation pathway. Consistent this, knockdown alleviated caused How then activity linked autophagy? Strikingly, Ref(2)P missing link two processes. was initially refractory locus sigma virus but later adaptor. It homolog p62, which contributes elimination specific substrates selective autophagy. reveal mammals, degraded consequence Ref(2)P, accumulates puncta enterocytes. at level connection comes light. Observations proteomic coupled additional biochemical experiments binds Dachs, atypical myosin negatively regulated cadherin fat. wing disc, Dachs inactivating Warts, core co-stabilize each other recruits auto-phagolysosomes degrade Dachs. Thus, results accumulation provoking production (see Figure 1). one keep check dysplasia. harbors symbiotic bacteria kept under microbicidal ROS antimicrobial peptides. well established microbiota stimulates observed removing raising axenically all phenotypes, implicating They showed induces NADPH Duox provokes removal Dachs/Ref(2)P prevents indigenous Collectively, reveals requirement spontaneous dysregulation microbiota-induced production. Mis-regulation without health, shortened lifespan, increased permeability, overactive immunity. unexpected raises question produced complex. sense either ROS-induced damage promote Dachs/Ref(2)P, removed Alternatively, directly autophagy, facilitating substrate here, protect paraquat-induced induction Whether needs elucidated. activates Atg4 oxidation Cys81 residue (Scherz-Shouval 2007Scherz-Shouval R. Shvets E. Fass Shorer Gil Reactive essential specifically Atg4.EMBO 2007; 26: 1749-1760Crossref (1532) While define linear linking Ref (2)P, likely global impact homeostasis. Dysfunctional contributing diseases, ulcerative colitis, still debated (Iida 2017Iida Onodera Nakase Role pathogenesis disease.World Gastroenterol. 23: 1944-1953Crossref (69) Interestingly, mice exacerbated pathology, elevated secretion, apoptosis (Burger 2018Burger Araujo López-Yglesias Rajala M.W. Geng Levine Hooper L.V. Burstein Yarovinsky F. Loss Paneth Causes Acute Susceptibility Toxoplasma gondii-Mediated Inflammation.Cell Host Microbe. 177-190.e4Abstract (47) Scholar), phenotype similar those described Scholar. would interesting test p62 models. Future work will shed light complex epithelium, health conditions. Regulation ROS-Triggered Pathway Autophagic Clearance IntestineNagai al.Developmental CellJanuary 4, 2021In BriefAutophagy maintaining intestine. al. secreted continuously stimulate regeneration, suppressed defect causes Ref(2)P/p62-mediated resulting accelerated age-related disorders. Full-Text