Mitochondria at the interface between danger signaling and metabolism: Role of unfolded protein responses in chronic inflammation

Inflammatory Bowel Diseases

Volumn 18, Issue 7, 2012, Pages 1364-1377

  Rath, Eva ^a   Haller, Dirk ^a  

^a TECHNICAL UNIVERSITY OF MUNICH   (Germany)

Author keywords

Endoplasmic reticulum; Mitochondrial dysfunction; Unfolded protein response

Indexed keywords

AUTOPHAGY; CELL METABOLISM; CELL SURVIVAL; CELLULAR STRESS RESPONSE; CHRONIC INFLAMMATION; DISORDERS OF MITOCHONDRIAL FUNCTIONS; ENDOPLASMIC RETICULUM; ENTERITIS; HUMAN; IMMUNE RESPONSE; INNATE IMMUNITY; MITOCHONDRION; NONHUMAN; OXIDATIVE STRESS; PATHOGENESIS; PRIORITY JOURNAL; PROTEIN HOMEOSTASIS; REVIEW; SIGNAL TRANSDUCTION; UNFOLDED PROTEIN RESPONSE;

ANIMALS; CHRONIC DISEASE; ENDOPLASMIC RETICULUM; HUMANS; INFLAMMATION; MITOCHONDRIA; SIGNAL TRANSDUCTION; UNFOLDED PROTEIN RESPONSE;

EID: 84862217471     PISSN: 10780998     EISSN: 15364844     Source Type: Journal    
DOI: 10.1002/ibd.21944     Document Type: Review

References (175)

1. Ma Y, Hendershot LM. The role of the unfolded protein response in tumour development: friend or foe? Nat Rev Cancer. 2004;4: 966-977. (Pubitemid 39626220)
2. Zhang K, Kaufman RJ. From endoplasmic-reticulum stress to the inflammatory response. Nature. 2008;454:455-462.
3. Ozcan U, Cao Q, Yilmaz E, et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science. 2004;306:457-461. (Pubitemid 39372439)
4. Hood DA, Irrcher I, Ljubicic V, et al. Coordination of metabolic plasticity in skeletal muscle. J Exp Biol. 2006;209:2265-2275. (Pubitemid 44065521)
5. Yoshida H. ER stress response, peroxisome proliferation, mitochondrial unfolded protein response and Golgi stress response. IUBMB Life. 2009;61:871-879.
6. Bukau B, Weissman J, Horwich A. Molecular chaperones and protein quality control. Cell. 2006;125:443-451.
7. Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol. 2007;8:519-529. (Pubitemid 46985379)
8. Ryan MT, Hoogenraad NJ. Mitochondrial-nuclear communications. Annu Rev Biochem. 2007;76:701-722.
9. Hartl FU, Hayer-Hartl M. Molecular chaperones in the cytosol: from nascent chain to folded protein. Science. 2002;295:1852-1858. (Pubitemid 34214115)
10. Yoneda T, Benedetti C, Urano F, et al. Compartment-specific perturbation of protein handling activates genes encoding mitochondrial chaperones. J Cell Sci. 2004;117:4055-4066. (Pubitemid 39328294)
11. Zhao Q, Wang J, Levichkin IV, et al. A mitochondrial specific stress response in mammalian cells. EMBO J. 2002;21:4411-4419. (Pubitemid 34984328)
12. Martinus RD, Garth GP, Webster TL, et al. Selective induction of mitochondrial chaperones in response to loss of the mitochondrial genome. Eur J Biochem. 1996;240:98-103.
13. Haynes CM, Petrova K, Benedetti C, et al. ClpP mediates activation of a mitochondrial unfolded protein response in C. elegans. Dev Cell. 2007;13:467-480. (Pubitemid 47500805)
14. Rath E, Berger E, Messlik A, et al. Induction of dsRNA-activated protein kinase links mitochondrial unfolded protein response to the pathogenesis of intestinal inflammation. Gut 2011.
15. Nakamura T, Furuhashi M, Li P, et al. Double-stranded RNA-dependent protein kinase links pathogen sensing with stress and metabolic homeostasis. Cell. 2010;140:338-348.
16. Horibe T, Hoogenraad NJ. The chop gene contains an element for the positive regulation of the mitochondrial unfolded protein response. PLoS ONE. 2007;2:e835.
17. Aldridge JE, Horibe T, Hoogenraad NJ. Discovery of genes activated by the mitochondrial unfolded protein response (mtUPR) and cognate promoter elements. PLoS ONE. 2007;2:e874.
18. Pizzo P, Pozzan T. Mitochondria-endoplasmic reticulum choreography: structure and signaling dynamics. Trends Cell Biol. 2007;17:511-517. (Pubitemid 47562768)
19. Hori O, Ichinoda F, Tamatani T, et al. Transmission of cell stress from endoplasmic reticulum to mitochondria: enhanced expression of Lon protease. J Cell Biol. 2002;157:1151-1160. (Pubitemid 34847786)
20. Bouman L, Schlierf A, Lutz AK, et al. Parkin is transcriptionally regulated by ATF4: evidence for an interconnection between mitochondrial stress and ER stress. Cell Death Differ. 2011;18:769-782.
21. Haga N, Saito S, Tsukumo Y, et al. Mitochondria regulate the unfolded protein response leading to cancer cell survival under glucose deprivation conditions. Cancer Sci. 2010;101:1135-1142.
22. Arduino DM, Esteves AR, Domingues AF, et al. ER-mediated stress induces mitochondrial-dependent caspases activation in NT2 neuron-like cells. BMB Rep. 2009;42:719-724.
23. Lim JH, Lee HJ, Ho Jung M, et al. Coupling mitochondrial dysfunction to endoplasmic reticulum stress response: a molecular mechanism leading to hepatic insulin resistance. Cell Signal. 2009;21: 169-177.
24. Kaser A, Lee AH, Franke A, et al. XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell. 2008;134:743-756.
25. Fukushima K, Fiocchi C. Paradoxical decrease of mitochondrial DNA deletions in epithelial cells of active ulcerative colitis patients. Am J Physiol Gastrointest Liver Physiol. 2004;286: G804-813. (Pubitemid 38506813)
26. Zhou R, Yazdi AS, Menu P, et al. A role for mitochondria in NLRP3 inflammasome activation. Nature. 2011;469:221-225.
27. Seth RB, Sun L, Ea CK, et al. Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. Cell. 2005;122:669-682. (Pubitemid 41242633)
28. Schroder K, Tschopp J. The inflammasomes. Cell. 2010;140: 821-832.
29. Nakahira K, Haspel JA, Rathinam VA, et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol. 2011;12:222-230.
30. Yoshida H, Matsui T, Hosokawa N, et al. A time-dependent phase shift in the mammalian unfolded protein response. Dev Cell. 2003;4: 265-271. (Pubitemid 36221802)
31. Calfon M, Zeng H, Urano F, et al. IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature. 2002;415:92-96. (Pubitemid 34062456)
32. Lee AH, Iwakoshi NN, Glimcher LH. XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol Cell Biol. 2003;23:7448-7459. (Pubitemid 37271447)
33. Yamamoto K, Sato T, Matsui T, et al. Transcriptional induction of mammalian ER quality control proteins is mediated by single or combined action of ATF6alpha and XBP1. Dev Cell. 2007;13:365-376. (Pubitemid 47308680)
34. Shaffer AL, Shapiro-Shelef M, Iwakoshi NN, et al. XBP1, downstream of Blimp-1, expands the secretory apparatus and other organelles, and increases protein synthesis in plasma cell differentiation. Immunity. 2004;21:81-93. (Pubitemid 38925269)
35. Sriburi R, Jackowski S, Mori K, et al. XBP1: a link between the unfolded protein response, lipid biosynthesis, and biogenesis of the endoplasmic reticulum. J Cell Biol. 2004;167:35-41. (Pubitemid 39363412)
36. Nishitoh H, Matsuzawa A, Tobiume K, et al. ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats. Genes Dev. 2002;16:1345-1355. (Pubitemid 34615088)
37. Urano F, Wang X, Bertolotti A, et al. Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science. 2000;287:664-666. (Pubitemid 30070916)
38. Harding HP, Zhang Y, Ron D. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature. 1999; 397:271-274. (Pubitemid 29051178)
39. Harding HP, Zhang Y, Bertolotti A, et al. Perk is essential for translational regulation and cell survival during the unfolded protein response. Mol Cell. 2000;5:897-904.
40. Brookes PS, Levonen AL, Shiva S, et al. Mitochondria: regulators of signal transduction by reactive oxygen and nitrogen species. Free Radic Biol Med. 2002;33:755-764. (Pubitemid 35232311)
41. Cullinan SB, Diehl JA. Coordination of ER and oxidative stress signaling: the PERK/Nrf2 signaling pathway. Int J Biochem Cell Biol. 2006;38:317-332. (Pubitemid 41821881)
42. Cullinan SB, Zhang D, Hannink M, et al. Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival. Mol Cell Biol. 2003;23:7198-7209. (Pubitemid 37211002)
43. Chen X, Shen J, Prywes R. The luminal domain of ATF6 senses endoplasmic reticulum (ER) stress and causes translocation of ATF6 from the ER to the Golgi. J Biol Chem. 2002;277:13045-13052. (Pubitemid 34952673)
44. Yoshida H, Haze K, Yanagi H, et al. Identification of the cis-acting endoplasmic reticulum stress response element responsible for transcriptional induction of mammalian glucose-regulated proteins. Involvement of basic leucine zipper transcription factors. J Biol Chem. 1998;273:33741-33749.
45. Kokame K, Kato H, Miyata T. Identification of ERSE-II, a new cisacting element responsible for the ATF6-dependent mammalian unfolded protein response. J Biol Chem. 2001;276:9199-9205.
46. Bommiasamy H, Back SH, Fagone P, et al. ATF6alpha induces XBP1-independent expansion of the endoplasmic reticulum. J Cell Sci. 2009;122:1626-1636.
47. Rutkowski DT, Arnold SM, Miller CN, et al. Adaptation to ER stress is mediated by differential stabilities of pro-survival and pro-apoptotic mRNAs and proteins. PLoS Biol. 2006;4:e374.
48. Szegezdi E, Logue SE, Gorman AM, et al. Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep. 2006;7:880-885. (Pubitemid 44523966)
49. Arco AD, Satrustegui J. New mitochondrial carriers: an overview. Cell Mol Life Sci. 2005;62:2204-2227. (Pubitemid 41500539)
50. Frey TG, Mannella CA. The internal structure of mitochondria. Trends Biochem Sci. 2000;25:319-324.
51. Webb CT, Gorman MA, Lazarou M, et al. Crystal structure of the mitochondrial chaperone TIM9.10 reveals a six-bladed alpha-propeller. Mol Cell. 2006;21:123-133. (Pubitemid 43017854)
52. Koehler CM, Beverly KN, Leverich EP. Redox pathways of the mitochondrion. Antioxid Redox Signal. 2006;8:813-822. (Pubitemid 44036499)
53. Hoogenraad NJ, Ward LA, Ryan MT. Import and assembly of proteins into mitochondria of mammalian cells. Biochim Biophys Acta. 2002;1592:97-105. (Pubitemid 35015169)
54. Ryan MT, Pfanner N. Hsp70 proteins in protein translocation. Adv Protein Chem. 2001;59:223-242. (Pubitemid 34169306)
55. Wiedemann N, Frazier AE, Pfanner N. The protein import machinery of mitochondria. J Biol Chem. 2004;279:14473-14476. (Pubitemid 38618831)
56. Martinus RD, Ryan MT, Naylor DJ, et al. Role of chaperones in the biogenesis and maintenance of the mitochondrion. FASEB J. 1995;9: 371-378.
57. Voos W, Rottgers K. Molecular chaperones as essential mediators of mitochondrial biogenesis. Biochim Biophys Acta. 2002;1592: 51-62. (Pubitemid 35015165)
58. Cocheme HM, Murphy MP. Complex I is the major site of mitochondrial superoxide production by paraquat. J Biol Chem. 2008; 283:1786-1798.
59. Broadley SA, Hartl FU. Mitochondrial stress signaling: a pathway unfolds. Trends Cell Biol. 2008;18:1-4.
60. Benedetti C, Haynes CM, Yang Y, et al. Ubiquitin-like protein 5 positively regulates chaperone gene expression in the mitochondrial unfolded protein response. Genetics. 2006;174:229-239. (Pubitemid 44427668)
61. Haynes CM, Yang Y, Blais SP, et al. The matrix peptide exporter HAF-1 signals a mitochondrial UPR by activating the transcription factor ZC376.7 in C. elegans. Mol Cell. 2010;37:529-540.
62. Young L, Leonhard K, Tatsuta T, et al. Role of the ABC transporter Mdl1 in peptide export from mitochondria. Science. 2001;291: 2135-2138. (Pubitemid 32224441)
63. Haynes CM, Ron D. The mitochondrial UPR - protecting organelle protein homeostasis. J Cell Sci. 2010;123:3849-3855.
64. Garcia MA, Gil J, Ventoso I, et al. Impact of protein kinase PKR in cell biology: from antiviral to antiproliferative action. Microbiol Mol Biol Rev. 2006;70:1032-1060. (Pubitemid 44958263)
65. Lee ES, Yoon CH, Kim YS, et al. The double-strand RNA-dependent protein kinase PKR plays a significant role in a sustained ER stress-induced apoptosis. FEBS Lett. 2007;581:4325-4332. (Pubitemid 47301867)
66. Takada Y, Ichikawa H, Pataer A, et al. Genetic deletion of PKR abrogates TNF-induced activation of IkappaBalpha kinase, JNK, Akt and cell proliferation but potentiates p44/p42 MAPK and p38 MAPK activation. Oncogene. 2007;26:1201-1212.
67. Shirihai OS, Gregory T, Yu C, et al. ABC-me: a novel mitochondrial transporter induced by GATA-1 during erythroid differentiation. EMBO J. 2000;19:2492-2502. (Pubitemid 30323539)
68. Leary SC, Shoubridge EA. Mitochondrial biogenesis: which part of "NO" do we understand? Bioessays. 2003;25:538-541. (Pubitemid 36702322)
69. Butow RA, Avadhani NG. Mitochondrial signaling: the retrograde response. Mol Cell. 2004;14:1-15. (Pubitemid 38469905)
70. Wallace DC. A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet. 2005;39:359-407. (Pubitemid 43011120)
71. Ojuka EO, Jones TE, Han DH, et al. Raising Ca2+ in L6 myotubes mimics effects of exercise on mitochondrial biogenesis in muscle. FASEB J. 2003;17:675-681. (Pubitemid 37221153)
72. Brookes PS, Kraus DW, Shiva S, et al. Control of mitochondrial respiration by NO*, effects of low oxygen and respiratory state. J Biol Chem. 2003;278:31603-31609. (Pubitemid 37048338)
73. Zong H, Ren JM, Young LH, et al. AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation. Proc Natl Acad Sci U S A. 2002;99: 15983-15987. (Pubitemid 35462735)
74. Puigserver P, Spiegelman BM. Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): transcriptional coactivator and metabolic regulator. Endocr Rev. 2003;24:78-90. (Pubitemid 36223280)
75. Lin J, Handschin C, Spiegelman BM. Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab. 2005;1: 361-370. (Pubitemid 43960626)
76. Kelly DP, Scarpulla RC. Transcriptional regulatory circuits controlling mitochondrial biogenesis and function. Genes Dev. 2004;18: 357-368. (Pubitemid 38316342)
77. Nakashima-Kamimura N, Asoh S, Ishibashi Y, et al. MIDAS/GPP34, a nuclear gene product, regulates total mitochondrial mass in response to mitochondrial dysfunction. J Cell Sci. 2005;118:5357-5367. (Pubitemid 41819597)
78. Chen H, Chomyn A, Chan DC. Disruption of fusion results in mitochondrial heterogeneity and dysfunction. J Biol Chem. 2005;280: 26185-26192. (Pubitemid 41022214)
79. Pich S, Bach D, Briones P, et al. The Charcot-Marie-Tooth type 2A gene product, Mfn2, up-regulates fuel oxidation through expression of OXPHOS system. Hum Mol Genet. 2005;14:1405-1415. (Pubitemid 40823451)
80. Campello S, Lacalle RA, Bettella M, et al. Orchestration of lymphocyte chemotaxis by mitochondrial dynamics. J Exp Med. 2006;203: 2879-2886. (Pubitemid 46026165)
81. Amiri M, Hollenbeck PJ. Mitochondrial biogenesis in the axons of vertebrate peripheral neurons. Dev Neurobiol. 2008;68:1348-1361.
82. Chen H, Detmer SA, Ewald AJ, et al. Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. J Cell Biol. 2003;160:189-200. (Pubitemid 36254953)
83. Chen H, Vermulst M, Wang YE, et al. Mitochondrial fusion is required for mtDNA stability in skeletal muscle and tolerance of mtDNA mutations. Cell. 2010;141:280-289.
84. Twig G, Elorza A, Molina AJ, et al. Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J. 2008;27:433-446. (Pubitemid 351161653)
85. Gu Y, Wang C, Cohen A. Effect of IGF-1 on the balance between autophagy of dysfunctional mitochondria and apoptosis. FEBS Lett. 2004;577:357-360. (Pubitemid 39535313)
86. Youle RJ, Narendra DP. Mechanisms of mitophagy. Nat Rev Mol Cell Biol. 2011;12:9-14.
87. Narendra D, Tanaka A, Suen DF, et al. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol. 2008;183:795-803.
88. Komatsu M, Waguri S, Ueno T, et al. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J Cell Biol. 2005;169:425-434. (Pubitemid 40686693)
89. Matsumoto N, Ezaki J, Komatsu M, et al. Comprehensive proteomics analysis of autophagy-deficient mouse liver. Biochem Biophys Res Commun. 2008;368:643-649.
90. Simmen T, Lynes EM, Gesson K, et al. Oxidative protein folding in the endoplasmic reticulum: tight links to the mitochondria-associated membrane (MAM). Biochim Biophys Acta. 2010;1798:1465-1473.
91. Gilady SY, Bui M, Lynes EM, et al. Ero1alpha requires oxidizing and normoxic conditions to localize to the mitochondria-associated membrane (MAM). Cell Stress Chaperones. 2010;15:619-629.
92. Myhill N, Lynes EM, Nanji JA, et al. The subcellular distribution of calnexin is mediated by PACS-2. Mol Biol Cell. 2008;19:2777-2788.
93. Hayashi T, Rizzuto R, Hajnoczky G, et al. MAM: more than just a housekeeper. Trends Cell Biol. 2009;19:81-88.
94. Princiotta MF, Finzi D, Qian SB, et al. Quantitating protein synthesis, degradation, and endogenous antigen processing. Immunity. 2003;18:343-354. (Pubitemid 36351514)
95. Culic O, Gruwel ML, Schrader J. Energy turnover of vascular endothelial cells. Am J Physiol. 1997;273:C205-213.
96. Csordas G, Thomas AP, Hajnoczky G. Quasi-synaptic calcium signal transmission between endoplasmic reticulum and mitochondria. EMBO J. 1999;18:96-108. (Pubitemid 29005027)
97. Hajnoczky G, Csordas G, Madesh M, et al. The machinery of local Ca2+ signalling between sarco-endoplasmic reticulum and mitochondria. J Physiol. 2000;529(Pt 1):69-81.
98. Deniaud A, Sharaf el dein O, Maillier E, et al. Endoplasmic reticulum stress induces calcium-dependent permeability transition, mitochondrial outer membrane permeabilization and apoptosis. Oncogene. 2008;27:285-299.
99. Gething MJ. Role and regulation of the ER chaperone BiP. Semin Cell Dev Biol. 1999;10:465-472.
100. Griffiths EJ, Rutter GA. Mitochondrial calcium as a key regulator of mitochondrial ATP production in mammalian cells. Biochim Biophys Acta. 2009;1787:1324-1333.
101. Tu BP, Weissman JS. The FAD- and O(2)-dependent reaction cycle of Ero1-mediated oxidative protein folding in the endoplasmic reticulum. Mol Cell. 2002;10:983-994. (Pubitemid 35453820)
102. Pagani M, Fabbri M, Benedetti C, et al. Endoplasmic reticulum oxidoreductin 1-lbeta (ERO1-Lbeta), a human gene induced in the course of the unfolded protein response. J Biol Chem. 2000;275: 23685-23692. (Pubitemid 30624653)
103. Cabibbo A, Pagani M, Fabbri M, et al. ERO1-L, a human protein that favors disulfide bond formation in the endoplasmic reticulum. J Biol Chem. 2000;275:4827-4833. (Pubitemid 30108874)
104. Manthey KC, Chew YC, Zempleni J. Riboflavin deficiency impairs oxidative folding and secretion of apolipoprotein B-100 in HepG2 cells, triggering stress response systems. J Nutr. 2005;135: 978-982. (Pubitemid 40638294)
105. Simmen T, Aslan JE, Blagoveshchenskaya AD, et al. PACS-2 controls endoplasmic reticulum-mitochondria communication and Bid-mediated apoptosis. EMBO J. 2005;24:717-729. (Pubitemid 40396102)
106. Szabadkai G, Bianchi K, Varnai P, et al. Chaperone-mediated coupling of endoplasmic reticulum and mitochondrial Ca2+ channels. J Cell Biol. 2006;175:901-911. (Pubitemid 44969196)
107. de Brito OM, Scorrano L. Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature. 2008;456:605-610.
108. Nicholas SA, Coughlan K, Yasinska I, et al. Dysfunctional mitochondria contain endogenous high-affinity human Toll-like receptor 4 (TLR4) ligands and induce TLR4-mediated inflammatory reactions. Int J Biochem Cell Biol. 2011;43:674-681.
109. Burkart A, Shi X, Chouinard M, et al. Adenylate kinase 2 links mitochondrial energy metabolism to the induction of the unfolded protein response. J Biol Chem. 2011;286:4081-4089.
110. Cakir Y, Ballinger SW. Reactive species-mediated regulation of cell signaling and the cell cycle: the role of MAPK. Antioxid Redox Signal. 2005;7:726-740. (Pubitemid 40563213)
111. Sorbara MT, Girardin SE. Mitochondrial ROS fuel the inflammasome. Cell Res. 2011;21:558-560.
112. Woo CH, Lim JH, Kim JH. Lipopolysaccharide induces matrix metalloproteinase-9 expression via a mitochondrial reactive oxygen species- p38 kinase-activator protein-1 pathway in Raw 264.7 cells. J Immunol. 2004;173:6973-6980. (Pubitemid 39541086)
113. Jones RG, Plas DR, Kubek S, et al. AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol Cell. 2005;18: 283-293. (Pubitemid 41350534)
114. McBride HM, Neuspiel M, Wasiak S. Mitochondria: more than just a powerhouse. Curr Biol. 2006;16:R551-560. (Pubitemid 44066793)
115. Kepp O, Galluzzi L, Kroemer G. Mitochondrial control of the NLRP3 inflammasome. Nat Immunol. 2011;12:199-200.
116. Sen A, Pruijssers AJ, Dermody TS, et al. The early interferon response to rotavirus is regulated by PKR and depends on MAVS/IPS-1, RIG-I, MDA-5, and IRF3. J Virol. 2011;85: 3717-3732.
117. Villani AC, Lemire M, Fortin G, et al. Common variants in the NLRP3 region contribute to Crohn's disease susceptibility. Nat Genet. 2009;41:71-76.
118. Zhernakova A, Festen EM, Franke L, et al. Genetic analysis of innate immunity in Crohn's disease and ulcerative colitis identifies two susceptibility loci harboring CARD9 and IL18RAP. Am J Hum Genet. 2008;82:1202-1210.
119. Monteleone G, Trapasso F, Parrello T, et al. Bioactive IL-18 expression is up-regulated in Crohn's disease. J Immunol. 1999;163: 143-147. (Pubitemid 29295835)
120. Pizarro TT, Michie MH, Bentz M, et al. IL-18, a novel immunoregulatory cytokine, is up-regulated in Crohn's disease: expression and localization in intestinal mucosal cells. J Immunol. 1999;162: 6829-6835. (Pubitemid 29309411)
121. Casini-Raggi V, Kam L, Chong YJ, et al. Mucosal imbalance of IL-1 and IL-1 receptor antagonist in inflammatory bowel disease. A novel mechanism of chronic intestinal inflammation. J Immunol. 1995;154:2434-2440.
122. Siegmund B, Lehr HA, Fantuzzi G, et al. IL-1 beta-converting enzyme (caspase-1) in intestinal inflammation. Proc Natl Acad Sci U S A. 2001;98:13249-13254. (Pubitemid 33051348)
123. Siegmund B, Fantuzzi G, Rieder F, et al. Neutralization of interleukin-18 reduces severity in murine colitis and intestinal IFN-gamma and TNF-alpha production. Am J Physiol Regul Integr Comp Physiol. 2001;281:R1264-1273.
124. Ferretti M, Casini-Raggi V, Pizarro TT, et al. Neutralization of endogenous IL-1 receptor antagonist exacerbates and prolongs inflammation in rabbit immune colitis. J Clin Invest. 1994;94: 449-453. (Pubitemid 24218125)
125. Saitoh T, Fujita N, Jang MH, et al. Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. Nature. 2008;456:264-268.
126. artor RB. Mechanisms of disease: pathogenesis of Crohn's disease and ulcerative colitis. Nat Clin Pract Gastroenterol Hepatol. 2006;3: 390-407.
127. Clavel T, Haller D. Bacteria- and host-derived mechanisms to control intestinal epithelial cell homeostasis: implications for chronic inflammation. Inflamm Bowel Dis. 2007;13:1153-1164. (Pubitemid 47402601)
128. Shkoda A, Ruiz PA, Daniel H, et al. Interleukin-10 blocked endoplasmic reticulum stress in intestinal epithelial cells: impact on chronic inflammation. Gastroenterology. 2007;132:190-207. (Pubitemid 46108743)
129. Heazlewood CK, Cook MC, Eri R, et al. Aberrant mucin assembly in mice causes endoplasmic reticulum stress and spontaneous inflammation resembling ulcerative colitis. PLoS Med. 2008;5:e54.
130. Beltran B, Nos P, Dasi F, et al. Mitochondrial dysfunction, persistent oxidative damage, and catalase inhibition in immune cells of naive and treated Crohn's disease. Inflamm Bowel Dis. 2010;16:76-86.
131. Martinon F, Chen X, Lee AH, et al. TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages. Nat Immunol. 2010;11:411-418.
132. Deng J, Lu PD, Zhang Y, et al. Translational repression mediates activation of nuclear factor kappa B by phosphorylated translation initiation factor 2. Mol Cell Biol. 2004;24:10161-10168. (Pubitemid 39507856)
133. Rao RV, Ellerby HM, Bredesen DE. Coupling endoplasmic reticulum stress to the cell death program. Cell Death Differ. 2004;11:372-380. (Pubitemid 38489415)
134. Hu P, Han Z, Couvillon AD, et al. Autocrine tumor necrosis factor alpha links endoplasmic reticulum stress to the membrane death receptor pathway through IRE1alpha-mediated NF-kappaB activation and down-regulation of TRAF2 expression. Mol Cell Biol. 2006;26:3071-3084.
135. Hotamisligil GS. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell. 2010;140:900-917.
136. Bertolotti A, Wang X, Novoa I, et al. Increased sensitivity to dextran sodium sulfate colitis in IRE1beta-deficient mice. J Clin Invest. 2001;107:585-593. (Pubitemid 32205179)
137. Hampe J, Franke A, Rosenstiel P, et al. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat Genet. 2007;39:207-211. (Pubitemid 46184351)
138. Rioux JD, Xavier RJ, Taylor KD, et al. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat Genet. 2007;39:596-604. (Pubitemid 46676115)
139. Consortium TWTCC. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007;447:661-678.
140. Parkes M, Barrett JC, Prescott NJ, et al. Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility. Nat Genet. 2007;39:830-832. (Pubitemid 47014496)
141. Hugot JP, Chamaillard M, Zouali H, et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature. 2001;411:599-603. (Pubitemid 32531408)
142. Ogura Y, Bonen DK, Inohara N, et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature. 2001;411:603-606. (Pubitemid 32531409)
143. Franchimont D, Vermeire S, El Housni H, et al. Deficient host-bacteria interactions in inflammatory bowel disease? The Toll-like receptor (TLR)-4 Asp299gly polymorphism is associated with Crohn's disease and ulcerative colitis. Gut. 2004;53:987-992. (Pubitemid 38824157)
144. Yu X, Wieczorek S, Franke A, et al. Association of UCP2-866 G/A polymorphism with chronic inflammatory diseases. Genes Immun. 2009;10:601-605.
145. Cadwell K, Liu JY, Brown SL, et al. A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature. 2008;456:259-263.
146. Wehkamp J, Salzman NH, Porter E, et al. Reduced Paneth cell alpha-defensins in ileal Crohn's disease. Proc Natl Acad Sci U S A. 2005;102:18129-18134. (Pubitemid 41798513)
147. Kaser A, Blumberg RS. Paneth cells and inflammation dance together in Crohn's disease. Cell Res. 2008;18:1160-1162.
148. Travassos LH, Carneiro LA, Ramjeet M, et al. Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry. Nat Immunol. 2010;11:55-62.
149. Singh SB, Ornatowski W, Vergne I, et al. Human IRGM regulates autophagy and cell-autonomous immunity functions through mitochondria. Nat Cell Biol. 2010;12:1154-1165.
150. Pecqueur C, Bui T, Gelly C, et al. Uncoupling protein-2 controls proliferation by promoting fatty acid oxidation and limiting glycolysis-derived pyruvate utilization. FASEB J. 2008;22: 9-18.
151. Brand MD, Esteves TC. Physiological functions of the mitochondrial uncoupling proteins UCP2 and UCP3. Cell Metab. 2005;2:85-93.
152. Emre Y, Nubel T. Uncoupling protein UCP2: when mitochondrial activity meets immunity. FEBS Lett. 2010;584:1437-1442.
153. Emre Y, Hurtaud C, Nubel T, et al. Mitochondria contribute to LPS-induced MAPK activation via uncoupling protein UCP2 in macrophages. Biochem J. 2007;402:271-278. (Pubitemid 46383424)
154. Singh R, Kaushik S, Wang Y, et al. Autophagy regulates lipid metabolism. Nature. 2009;458:1131-1135.
155. Barrett JC, Hansoul S, Nicolae DL, et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat Genet. 2008;40:955-962.
156. Rinaldo P, Matern D, Bennett MJ. Fatty acid oxidation disorders. Annu Rev Physiol. 2002;64:477-502. (Pubitemid 34259237)
157. Shekhawat PS, Srinivas SR, Matern D, et al. Spontaneous development of intestinal and colonic atrophy and inflammation in the carnitine-deficient jvs (OCTN2(-/-)) mice. Mol Genet Metab. 2007;92: 315-324. (Pubitemid 350123730)
158. Roediger WE, Nance S. Metabolic induction of experimental ulcerative colitis by inhibition of fatty acid oxidation. Br J Exp Pathol. 1986;67:773-782. (Pubitemid 17212913)
159. Kaser A, Zeissig S, Blumberg RS. Inflammatory bowel disease. Annu Rev Immunol. 2010;28:573-621.
160. He D, Sougioultzis S, Hagen S, et al. Clostridium difficile toxin A triggers human colonocyte IL-8 release via mitochondrial oxygen radical generation. Gastroenterology. 2002;122:1048-1057. (Pubitemid 34267287)
161. Kamizato M, Nishida K, Masuda K, et al. Interleukin 10 inhibits interferon gamma- and tumor necrosis factor alpha-stimulated activation of NADPH oxidase 1 in human colonic epithelial cells and the mouse colon. J Gastroenterol. 2009;44:1172-1184.
162. Lewis K, Lutgendorff F, Phan V, et al. Enhanced translocation of bacteria across metabolically stressed epithelia is reduced by butyrate. Inflamm Bowel Dis. 2010;16:1138-1148.
163. Nazli A, Yang PC, Jury J, et al. Epithelia under metabolic stress perceive commensal bacteria as a threat. Am J Pathol. 2004;164: 947-957. (Pubitemid 38235476)
164. Soderholm JD, Olaison G, Peterson KH, et al. Augmented increase in tight junction permeability by luminal stimuli in the non-inflamed ileum of Crohn's disease. Gut. 2002;50:307-313. (Pubitemid 34161043)
165. Schurmann G, Bruwer M, Klotz A, et al. Transepithelial transport processes at the intestinal mucosa in inflammatory bowel disease. Int J Colorectal Dis. 1999;14:41-46. (Pubitemid 29295302)
166. Mayer L. Evolving paradigms in the pathogenesis of IBD. J Gastroenterol. 2010;45:9-16.
167. Cresci GA, Thangaraju M, Mellinger JD, et al. Colonic gene expression in conventional and germ-free mice with a focus on the butyrate receptor GPR109A and the butyrate transporter SLC5A8. J Gastrointest Surg. 2010;14:449-461.
168. Tazoe H, Otomo Y, Karaki S, et al. Expression of short-chain fatty acid receptor GPR41 in the human colon. Biomed Res. 2009;30: 149-156.
169. Thangaraju M, Cresci GA, Liu K, et al. GPR109A is a G-protein-coupled receptor for the bacterial fermentation product butyrate and functions as a tumor suppressor in colon. Cancer Res. 2009;69: 2826-2832.
170. Maslowski KM, Vieira AT, Ng A, et al. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature. 2009;461:1282-1286.
171. Bugaut M. Occurrence, absorption and metabolism of short chain fatty acids in the digestive tract of mammals. Comp Biochem Physiol B. 1987;86:439-472.
172. Treem WR, Ahsan N, Shoup M, et al. Fecal short-chain fatty acids in children with inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 1994;18:159-164. (Pubitemid 24056473)
173. Baur P, Martin FP, Gruber L, et al. Metabolic Phenotyping of the Crohn's Disease-like IBD Etiopathology in the TNF(DeltaARE/WT) Mouse Model. J Proteome Res 2011.
174. Fung KY, Brierley GV, Henderson S, et al. Butyrate-induced apoptosis in HCT116 colorectal cancer cells includes induction of a cell stress response. J Proteome Res. 2011;10:1860-1869.
175. Kolar S, Barhoumi R, Jones CK, et al. Interactive effects of fatty acid and butyrate-induced mitochondrial Ca(2+) loading and apoptosis in colonocytes. Cancer. 2011 [Epub ahead of print].