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Autophagy Gives a Nod and a Wink to the Inflammasome and Paneth

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Autophagy Gives a Nod and a Wink to the Inflammasome and Paneth View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Developmental Cell Previews Autophagy Gives a Nod and a Wink to the Inflammasome and Paneth Cells in Crohn’s Disease Vojo Deretic,1,* Sharon Master,1 and Sudha Singh1 1Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, 915 Camino de Salud, The University of New Mexico, Albuquerque, NM 87131, USA *Correspondence: [email protected] DOI 10.1016/j.devcel.2008.10.012 Recent genome-wide association studies have linked polymorphisms in two atophagy genes, Atg16L1 and IRGM, with Crohn’s Disease. Now, experiments with Atg16L1 transgenic mice indicate multiple roles for autophagy in inflammatory bowel disease via effects on Paneth cells, a runaway inflammasome, and the proinflammatory cytokine IL-1b. Autophagy is a cytoplasmic homeostasis portion interacting with Atg5, the coiled- DCCD fetal liver-derived macrophages process that cleanses the interior of all coil domain (CCD) necessary for Atg16L1 for proinflammatory cytokine production eukaryotic cells. It turns over stable or oligomerization and Atg5-Atg12 associa- in response to LPS and found elevated aggregated proteins, removes surplus or tion, and the WD repeat domain, which IL-1b production (Figures 1B and 1C). Ex- damaged organelles, and eliminates intra- is absent in yeast. posure of Atg16L1 DCCD macrophages to cellular microbes (Levine and Deretic, Recent genome-wide association commensal bacteria such as Escherichia 2007). A hallmark feature of autophagy is (GWA) studies have linked autophagy coli elicited abnormally high IL-1b pro- the formation within the cytosol of mem- with Crohn’s Disease (CD), a major form cessing. Next, lethally irradiated mouse brane crescents corralling cytoplasmic of chronic inflammatory bowel disease chimeras reconstituted with Atg16L1 targets into the double-membrane-bound (Xavier and Podolsky, 2007). CD develops DCCD embryonic liver cells were sub- autophagosome, an emblematic feature predominantly at anatomical sites (termi- jected to experimentally induced colitis of autophagy. Autophagosomes fuse with nal ileum and colon) where commensal with dextran sulfate. The result was a lysosomes, thus degrading the captured bacteria dramatically increase in mass 100% 10-day mortality of the Atg16L1 cargo. Autophagy plays a role in aging, de- (Xavier and Podolsky, 2007). It is believed DCCD mouse chimeras, elevated IL-1b generative diseases, cancer, and immu- that CD results from a ‘‘perfect storm’’ of and IL-18 in the sera, and distal colon nity. In its immunological manifestations ongoing challenge by normal gut flora and inflammation. Death was avoided and (Levine and Deretic, 2007), autophagy an aberrant innate immunity response. pathology was reversed by IL-1b- and promotes MHC II antigen presentation of The latest GWA breakthroughs have IL-18-neutralizing antibodies (Saitoh endogenous antigens, acts as an effector expanded the role of innate immunity et al., 2008). of Th1/Th2 polarization, governs T cell components beyond the already impli- Can elevated IL-1b help understand CD repertoire and homeostasis, and acts as cated Nod2 (Kanneganti et al., 2007)to pathogenesis? The Atg16L1 DCCD ef- an antimicrobial mechanism that can be include autophagy based on association fects on IL-1b are reminiscent of CD Nod2 activated by Toll-like receptors (TLR) with Atg16L1 (Cadwell et al., 2008; Saitoh variants, which also elicit elevated IL-1b (Delgado et al., 2008). et al., 2008) and an autophagy-linked in murine models (Kanneganti et al., Autophagy is best understood in yeast, factor, IRGM, involved in clearing bacteria 2007). The components of IL-1b signaling which was the origin of the Atg nomencla- (Singh et al., 2006). are often abnormal in intestinal tissue ture used for many components of the Until the two new reports from the specimens from inflammatory bowel dis- pathway. Autophagosome formation in groups of Shizuo Akira (Saitoh et al., ease patients, and increased IL-1b may, eukaryotes is driven by two key Atg con- 2008) and Herbert Virgin (Cadwell et al., among other effects, increase epithelial jugation systems: (1) a covalent protein 2008), little was known (but much was be- barrier permeability (Al-Sadi et al., 2008), conjugate, Atg5-Atg12, noncovalently ing guessed) about the role of Atg16L1 possibly enhancing microbial product complexed with Atg16 (or Atg16L1 in and autophagy in CD. The two teams gen- translocation. Complementing these find- mammals); and (2) a protein-lipid conju- erated different Atg16L1 transgenic mice ings, the elegant studies by Saitoh et al. gate of Atg8 (LC3 in mammals) with phos- and came to diverse but not mutually ex- have also uncovered a previously unap- phatidylethanolamine at its C terminus. clusive conclusions. Saitoh et al. (2008) preciated role for autophagy in inflamma- The Atg5-Atg12/Atg16 complex stimu- generated Atg16L1 DCCD mice, with the some function. The inflammasome lates LC3 lipidation. In this process, Atg16L1 gene deleted for the CCD do- occupies a special place in the innate im- Atg16L1 ‘‘marks the spot’’ where the con- main. The Atg16L1 DCCD mice die within munity hall of fame. Upon proper stimula- jugation systems converge to generate 1 day of birth, a phenomenon previously tion, the inflammasome proteolytically nascent autophagosomes (Fujita et al., seen with the Atg5À/À knockout mice. converts inactive substrates into biologi- 2008). Mammalian Atg16L1 contains three Atg16L1-deficient MEFs were null for cally highly active inflammation media- distinct regions (Figure 1A): the N-terminal autophagy. Saitoh et al. tested Atg16L tors, which includes the processing of Developmental Cell 15, November 11, 2008 ª2008 Elsevier Inc. 641 Developmental Cell Previews pro-IL-1b into IL-1b. It now turns (Kuballa et al., 2008). In addition, out that autophagy downregu- the Atg16L1*300A protein was lates this system by a posttrans- unstable in infected epithelial lational mechanism requiring cells, a feature not seen with the reactive oxygen species and a protective Atg16L1*300T allele. TLR binding adaptor molecule Thus, Atg16L1*300A has a hypo- known as TRIF. Although the ex- morphic phenotype (Kuballa act details are not available yet, et al., 2008), meaning that it would be interesting to know Atg16L1HM mice may recapitu- whether autophagy targets the late some aspects of this inflammasome or its substrates Atg16L1 CD risk allele. Collec- for degradation. tively, these studies affirm sev- Anticipating that an outright eral long-term or recent notions Atg16L1 knockout would be about CD and provide insight lethal, Cadwell et al. (2008) took into the role of autophagy in this a different approach and gener- disease, an aspect that will ated hypomorphic Atg16L1HM Figure 1. Atg16L Roles in Crohn’s Disease become more complete once mice expressing Atg16L1 at (A) Schematic of Atg16L1 features. the effects of other autophagy (B) Normal ileal crypt of Lieberku¨ hn (CL) and villus (V). AØ, autophago- 30% of the wild-type levels. some (detected in cell culture); E, enterocyte; E.c., adherent-invasive factors, including IRGM, are The strategy resulted in viable E. coli; G, Goblet cell; MØ, macrophage; P, Paneth cell; SCZ, stem revealed. Atg16L1HM progeny. Autophagy cell zone; TJ, tight junction. (C) Dotted arrow, microbial translocation (proposed). 1.–3., effects of was reduced (but not completely ATG16L1 mutations. 1. Increased IL-1b activation (in macrophages REFERENCES eliminated) as shown in from Atg16L1 transgenic mice) accompanied by experimentally Atg16L1HM MEFs and ileal spec- induced intestinal inflammation and mortality in vivo (not shown). IL-1b can dilate tight junctions (demonstrated in vitro) and may en- Al-Sadi, R., Ye, D., Dokladny, K., and imens. Although Atg16L1 is ex- Ma, T.Y. (2008). J. Immunol. 180, hance microbial translocation. 2. Fewer granules or diffuse granule 5653–5661. pressed in both the crypt and contents in the cytoplasm of Paneth cells (in ileal sections from HM the villus of the ileum (Figure 1), Atg16L1 hypomorphic mice and uninvolved portions of ileocolic Cadwell, K., Liu, J.Y., Brown, S.L., changes were observed only in resection specimens from CD patients). 3. Reduced autophagy of Miyoshi, H., Loh, J., Lennerz, J.K., Kishi, invasive bacteria (in cultured epithelial cells rendered Atg16L1*300A Paneth cells, which have a previ- C., Kc, W., Carrero, J.A., Hunt, S., et al. by siRNA knockdown of endogenous Atg16L1 and complemented (2008). Nature, in press. Published ously suspected role in CD with Atg16L1*300A). online October 5, 2008. 10.1038/ (Xavier and Podolsky, 2007). nature07416. Paneth cells are found at bottom Delgado, M.A., Elmaoued, R.A., Davis, of ileal crypts (Figure 1B), and exocytose changes elsewhere in the epithelium. As A.S., Kyei, G., and Deretic, V. (2008). EMBO J. granules containing antimicrobial prod- with the studies by Saitoh et al., the 27, 1110–1121. HM ucts—a-defensins, lysozyme, and Atg16L1 findings by Cadwell et al. Fujita, N., Itoh, T., Omori, H., Fukuda, M., Noda, T., secretory phospholipase A2. These anti- showed parallels with Nod2 effects: and Yoshimori, T. (2008). Mol. Biol. Cell 19, microbials are believed to protect the expression in CD-like mutant Nod2 2092–2100. neighboring stem cells from microbial mouse alleles affects Paneth cells by Kanneganti, T.D., Lamkanfi, M., and Nunez, G. insults and keep gut microbial flora under reducing these cells’ Nod2-dependent (2007). Immunity 27, 549–559.
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