Soluble bioactive microbial mediators regulate proteasomal degradation and autophagy to protect against inflammation-induced stress

American Journal of Physiology - Gastrointestinal and Liver Physiology

Volumn 311, Issue 4, 2016, Pages G634-G647

  Inaba, Yuhei ^a,b   Ueno, Nobuhiro ^a,b   Numata, Masatsugu ^a,c   Zhu, Xiaorong ^a   Messer, Jeannette S ^a   Boone, David L ^d   Fujiya, Mikihiro ^b   Kohgo, Yutaka ^b   Musch, Mark W ^a   Chang, Eugene B ^a  

^a UNIVERSITY OF CHICAGO   (United States)

^b ASAHIKAWA MEDICAL COLLEGE   (Japan)

^c KAGOSHIMA UNIVERSITY   (Japan)

^d INDIANA UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Atg5; Atg7; Cell death; Cell survival; Host microbe interaction; Inflammatory bowel diseases; Microbiota; Microflora; Mucosal inflammation; Peptidoglycan

Indexed keywords

AUTOPHAGY PROTEIN 5; AUTOPHAGY PROTEIN 7; BIFIDOBACTERIUM BREVE SECRETED FACTOR; GASTROINTESTINAL AGENT; HEAT SHOCK PROTEIN 27; MITOGEN ACTIVATED PROTEIN KINASE; PROBIOTIC AGENT; PROTEASOME; PROTEIN; UNCLASSIFIED DRUG; AUTOPHAGY RELATED PROTEIN 5; AUTOPHAGY RELATED PROTEIN 7;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; AUTOPHAGY; BIFIDOBACTERIUM BREVE; CELL DEATH; CELL PROTECTION; CONDITIONED MEDIUM; CONTROLLED STUDY; DEXTRAN SODIUM SULFATE-INDUCED COLITIS; DRUG MECHANISM; ENZYME INHIBITION; HUMAN; HUMAN CELL; IN VITRO STUDY; IN VIVO STUDY; INFLAMMATION; INTESTINE EPITHELIUM CELL; INTESTINE INJURY; MOUSE; NONHUMAN; OXIDATIVE STRESS; PRIORITY JOURNAL; PROTEIN DEGRADATION; PROTEIN EXPRESSION; SIGNAL TRANSDUCTION; UPREGULATION; ANIMAL; CELL LINE; EPITHELIUM CELL; GENETICS; INTESTINE MUCOSA; KNOCKOUT MOUSE; METABOLISM; MICROBIOLOGY; PHYSIOLOGICAL STRESS; PHYSIOLOGY;

ANIMALS; AUTOPHAGY; AUTOPHAGY-RELATED PROTEIN 5; AUTOPHAGY-RELATED PROTEIN 7; BIFIDOBACTERIUM BREVE; CELL LINE; EPITHELIAL CELLS; INFLAMMATION; INTESTINAL MUCOSA; MICE; MICE, KNOCKOUT; PROTEASOME ENDOPEPTIDASE COMPLEX; SIGNAL TRANSDUCTION; STRESS, PHYSIOLOGICAL;

EID: 84990913006     PISSN: 01931857     EISSN: 15221547     Source Type: Journal    
DOI: 10.1152/ajpgi.00092.2016     Document Type: Article

References (89)

1. Adolph TE, Tomczak MF, Niederreiter L, Ko HJ, Bock J, Martinez- Naves E, Glickman JN, Tscurtschenthaler M, Hartwig J, Hosomi S, Fiak MB, Cusick JL, Kohno K, Iwawaki T, Billman-Born S, Raine T, Bharti R, Lucius R, Kweon MN, Marciniak SJ, Choi A, Hagen SJ, Schreiber S, Rosensteil P, Kaser A, Blumberg RS. Paneth cells as a site of origin for intestinal inflammation. Nature 503: 272–276, 2013.
2. Atarashi K, Tanoue T, Oshima K, Suda W, Nagano Y, Nishikawa H, Fukuda S, Saito T, Narushima S, Hase K, Kim S, Fritz JV, Wilmes P, Ueha S, Matsushima K, Ohno H, Olle B, Sakaguchi S, Taniguchi T, Morita H, Hattori M, Honda K. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 500: 232–236, 2013.
3. Basler M, Dajee M, Moll C, Groettrup M, Kirk CJ. Prevention of experimental colitis by a selective inhibitor of the immunoproteasome. J Immunol 185: 634–641, 2010.
4. Benbrook DM, Long A. Integration of autophagy, proteasomal degradation, unfolded protein response and apoptosis. Exp Oncol 34: 286–297, 2012.
5. Bertolotti A, Wang X, Novao I, Jungreis R, Schlessinger K, Cho JH, West AB, Ron D. Increased sensitivity to dextran sulfate sodium in IRE1beta deficient mice. J Clin Invest 107: 585–593, 2001.
6. Bjorkoy G, Lamark T, Brech A, Outzen H, Perander M, Overvatn A, Stenmark H, Johansen T. p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J Cell Biol 171: 603–614, 2005.
7. Boya P, Reggori F, Codogno P. Emerging regulation and functions of autophagy. Nat Cell Biol 15: 713–720, 2013.
8. Cabrera S, Fernandez AF, Marino G, Aguirre A, Suarez MF, Espanol Y, Vega JA, Laura R, Fueyo A, Fernandez-Garcia MS, Freije JM, Kroemer G, Lopez-Otin C. ATG4B/autophagin-1 regulates intestinal homeostasis and protects mice from experimental colitis. Autophagy 9: 1188–1200, 2013.
9. Calagno SR, Li S, Shalid MW, Wallace MB, Leitges M, Fields AP, Murray NR. PKC iota in the intestinal epithelium protects against DSS induced colitis. Inflamm Bowel Dis 17: 1685–1697, 2011.
10. Ciorba MA, Riehl TE, Rao MS, Moon C, Ee X, Nava GM, Walker MR, Marinshaw JM, Stappenbeck TS, Stenson WF. Lactobacillus probiotic protects intestinal epithelium from radiation injury in a TLR2- cyclooxygenase 2 dependent manner. Gut 61: 829–838, 2012.
11. Clarke R, Cook KL, Hu R, Facey CO, Tavassoly I, Schwartz JL, Baumann WT, Tyson JJ, Xuan J, Wang Y, Warri A, Shajahan AN. Endoplasmic reticulum stress, the unfolded protein response, autophagy, and the integrated regulation of breast cancer cell fate. Cancer Res 72: 1321–1338, 2012.
12. Collins JW, Akin AR, Kosta A, Zhang N, Tangney M, Francsi KP, Frankel G. Pretreatment with Bifidobacterium breve UCC2003 modulates Citrobacter rodentium induced colonic inflammation and organ specificity. Microbiology 158: 2826–2834, 2012.
13. Cooney RJ, Baker J, Brain O, Danis B, Pichulik T, Allan P, Gerguson DJ, Campbell BJ, Jewell D, Simmons A. NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nat Med 16: 90–97, 2010.
14. Ding WX, Ni HM, Gao W, Yoshimori T, Stolz DB, Ron D, Yin XM. Linking of autophagy to ubiquitin-proteasome system is important for the regulation of endoplasmic reticulum stress and cell viability. Am J Pathol 171: 513–524, 2007.
15. Dirisina R, Katzman RB, Goretsky T, Managlia E, Mittal N, Williams DB, Qiu W, Yu J, Chandel NS, Zhang L, Barrett TA. p53 and PUMA independently regulate apoptosis of intestinal epithelial cells in patients and mice with colitis. Gastroenterology 141: 1036–1045, 2011.
16. DiSabatino A, Ciccocioppo R, Luinette O, Rucevuti L, Morera R, Cifone MG, Solcia E, Corazza GR. Increased enterocyte apoptosis in inflamed areas of Crohn’s disease. Dis Colon Rectum 46: 1498–1507, 2003.
17. Elinav E, Strowig T, Kau AL, Henao-Meija J, Thaiss CA, Booth CJ, Peaper DR, Bertin J, Eisenbarth SC, Godron JI, Flavell RA. NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 145: 745–757, 2011.
18. Ewaschuk JB, Diaz H, Meddings L, Diederichs B, Dmytrash A, Backer J, Looijer-van Langen M, Madsen KL. Secreted factors from Bifidobacterium infantis enhance epithelial cell barrier function. Am J Physiol Gastrointest Liver Physiol 295: G1025–G1034, 2008.
19. Fanning S, Hall SJ, Van Sinderen D. Bifidobacterium breve UCC2003 surface exopolysaccharide production is a beneficial trait mediating commensal- host interaction through immune modulation and pathogen protection. Gut Microbes 3: 420–425, 2012.
20. Fujiwara M, Kaneko T, Iwana H, Taketomo N, Tsunoo H, Kanno J, Ohkusa T, Okayasu I. Inhibitory effects of Bifidobacterium longum on experimental ulcerative colitis induced in mice by synthetic dextran sulfate sodium. Digestion 67: 90–95, 2003.
21. Fujiya Musch MW M, Nakagawa Y, Hu S, Alverdy J, Kohgo Y, Schneewind O, Jabri B, Chang EB. The Bacillus subtilis quorumsensing molecule CSF contributes to intestinal homeostasis via OCTN2, a host cell membrane transport. Cell Host Microbe 1: 299–308, 2007.
22. Furusawa Y, Obata Y, Fukuda S, Endo TA, Nakato G, Takahashi D, Nakanishi Y, Uetake C, Kato K, Kato T, Takahashi M, Fukuda NN, Murakami S, Miyauchi E, Hino S, Atarashi K, Onawa S, Fujimura Y, Lockett T, Clarke JM, Topping DL, Tomita M, Hori S, Ohara O, Morita T, Koseki H, Kikuchi J, Honda K, Hase K, Ohno H. Commensal microbe derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504: 446–450, 2013.
23. Ge P, Zhang J, Wang X, Meng FK, Li WC, Luan YX, Ling F, Luo YN. Inhibition of autophagy induced by proteasome increases cell death in human SHG-44 cells. Acta Pharmacol Sin 30: 1046–1052, 2009.
24. Ghonime MG, Shamaa OR, Das S, Eldomany RA, Fernandes-Alnemri T, Alnemri ES, Gavrilin MA, Wewers MD. Inflammasome priming by lipopolysaccharide is dependent upon ERK signaling and proteasome function. J Immunol 192: 3881–3888, 2014.
25. Gump JM, Thorburn A. Autophagy and apoptosis: what is the connection. Trends Cell Biol 21: 387–392, 2011.
26. Hagiwara C, Tanaka M, Kudo H. Increase in colorectal epithelial apoptotic cells in patients with ulcerative colitis ultimately requiring surgery. J Gastroenterol Hepatol 17: 758–764, 2002.
27. Heuvelin E, Lebreton C, Grangette C, Pot B, Cerf-Bensussan N, Heyman M. Mechanisms involved in alleviation of intestinal inflammation by Bifidobacterium breve soluble factors. PLoS One 4: e5184, 2009.
28. Hidalgo-Cantabrana C, Nikolic M, Lopez P, Suárez A, Miljkovic M, Kojic M, Margolles A, Golic N, Ruas-Madiedo P. Exopolysaccharide producing Bifidobacterium animalis subsp. lactis strains and their polymers elicit different responses on immune cells from blood and gut associated lymphoid tissue. Anaerobe 26: 24–30, 2014.
29. Hoarau C, Martin L, Faugaret D, Baron C, Dauba A, Aubert-Jacquin C, Velge-Roussel F, Lebranchu Y. Supernatant from Bifidobacterium differentially modulates transduction signaling pathways for biological functions of human dendritic cells. PLoS One 3: e2753, 2008.
30. Hu S, Zhu X, Triggs JR, Tao Y, Wang Y, Lichtenstein L, Bissonnette M, Musch MW, Change EB. Inflammation induced 3=UTR depdendent translational inhibition of Hsp70 mRNA impairs intestinal homeostasis. Am J Physiol Gastrointest Liver Physiol 296: G1003–G1011, 2009.
31. Inoue S, Nakase H, Matsuura M, Mikami S, Ueno S, Uza N, Chiba T. The effect of proteasome inhibitor MG132 on experimental inflammatory bowel disease. Clin Exp Immunol 156: 172–182, 2009.
32. Iwabuchi N, Takahashi N, Xiao JZ, Miyaji K, Iwatsuki K. In vitro Th1 cytokine-independent Th2 supressive effects of bifidobacteria. Microbiol Immunol 51: 649–660, 2007.
33. Iwamoto M, Koji T, Makiyama K, Kobayashi N, Nakane PK. Apoptosis of crypt epithelial cells in ulcerative colitis. J Pathol 180: 152–159, 1996.
34. Jiang H, Sun J, Xu Q, Lie Y, m Wie J, Young CY, Yuan H, Lou H. Marchantin M: a novel inhibitor of proteasome induces autophagy cell death in prostate cancer cells. Cell Death Dis 4: e761, 2013.
35. Jones SE, Paynich ML, Knight KL. Exopolysaccharides: Sweet success with probiotic therapeutics. Inflamm Cell Signal 1: e334, 2014.
36. Kawazoe Y, Nakai A, Tanabe M, Nagata K. Proteasome inhibition leads to the activation of all members of the heat shock factor family. Eur J Biochem 255: 356–362, 1998.
37. Kojima K, Musch MW, Ren H, Boone DL, Hendrickson BA, Ma A, Chang EB. Enteric flora and lymphocyte-derived cytokines determine expression of heat shock proteins in mouse colonic epithelial cells. Gastroenterology 124: 1395–1407, 2003.
38. Komatsu M, Waguri S, Ueno T, Iwata J, Murata S, Tanida I, Ezaki J, Mizushima N, Ohsumi Y, Uchiyama Y, Kominami E, Tanaka K, Chiba T. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J Cell Biol 169: 425–434, 2005.
39. Korolchuk VI, Menzies FM, Rubinsztein DC. Mechanisms of cross-talk between the ubiquitin-proteasome and autophagy-lysosome systems. FEBS Lett 584: 1393–1398, 2010.
40. Lee JW, Juliano RL. 5α1 integrin protects intestinal epithelial cells from apoptosis through a phosphatidylinositol-3-kinase and protein kinase A dependent pathway. Mol Biol Cell 11: 1973–1987, 2000.
41. Levine B, Mizushima N, Virgin HW. Autophagy in immunity and inflammation. Nature 469: 323–335, 2011.
42. Lin R, Jiang Y, Zhao XY, Guan Y, Qian W, Fu XC, Ren HY, Hou XH. Four types of Bifidobacteria trigger autophagy response in intestinal epithelial cells. J Dig Dis 15: 597–605, 2014.
43. Liu W, Chen Y, Golan MA, Annuziata ML, Du J, Dougherty U, Kong J, Musch M, Huang Y, Pekow J, Zhneg C, Bissonnette M, Hanauer SB, Li YC. Intestinal epithelial vitamin D receptor signaling inhibits experimental colitis. J Clin Invest 123: 3983–3986, 2013.
44. Lopez P, Gueimonda M, Margolies A, Suarez A. Distinct Bifidobacterium strains drive different immune responses in vitro. Int J Food Microbiol 138: 157–165, 2010.
45. Lopez P, Gonzalez-Rodriguez I, Gueimonde M, Margolies A, Suarez A. Immune responses to Bifidobacterium bifidum strains support Treg/ Th17 plasticity. PLoS One 6: e24776, 2011.
46. Lopez P, Monteserin DC, Gueimonde M, de los Reyes-Gavilan CG, Margolies A, Suarez A, Ruas-Madiedo P. Exopolysaccharide producing Bifidobacterium strains elicit different responses upon interaction with human cells. Food Res Intl 46: 99–107, 2012.
47. Marin ML, Lee JH, Murtha J, Ustunol Z, Pestka JJ. Differential cytokine production in clonal macrophage and T-cell lines cultured with bifidobacteria. J Dairy Sci 80: 2713–2720, 1997.
48. Marino G, Niso-Santano M, Baehrecke EH, Kroemer G. Self-consumption: The interplay of autophagy and apoptosis. Nat Rev Mol Cell Biol 15: 81–94, 2014.
49. McConnell BB, Kim SS, Biakowska AB, Yu K, Sitaraman SV, Yang VW. Kruppel like factor 5 protects against dextran sulfate sodium induced colonic injury in mice by promoting epithelial repair. Gastroenterology 140: 540–549, 2011.
50. Murrow L, Debnath J. Autophagy as a stress response and quality control mechanism: Implications of cell injury and human disease. Annu Rev Pathol 24: 105–137, 2013.
51. Myeku N, Figueiredo-Pereira ME. Dynamics of the degradation of ubiquitinated proteins by proteasomes and autophagy: Association with sequestrosome 1/p62. J Biol Chem 286: 22426–22440, 2011.
52. Nagaraja GM, Kaur P, Neumann W, Asea EE, Bausero MA, Multhoff G, Asea A. Silencing Hsp25/Hsp27 gene expression augments proteasome activity and increases CD8_ T cell mediated tumor killing and memory responses. Cancer Prev Res 5: 122–137, 2012.
53. Neurath MF. New targets for mucosal healing and therapy in inflammatory bowel diseases. Mucosal Immunol 7: 6–19, 2014.
54. Ogata M, Hino S, Saito A, Morikawa K, Kondo S, Kanemoto S, Murakami T, Taniguchi M, Tanii I, Yoshinaga K, Shiosaka S, Hammarback JA, Urano F, Imaizumi K. Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol Cell Biol 26: 9220–9231, 2006.
55. Osman N, Adawi D, Ahrne S, Jeppsson B, Molin G. Modulation of the effect of dextran sulfate sodium induced acute colitis by different probiotic strains of Lactobacillus and Bifidobacterium. Dig Dis Sci 49: 320–327, 2004.
56. Osman N, Adawi D, Molin G, Ahrne S, Berggren A, Jeppsson B. Bifidobacterium infantis strains with and without a combination of oligofructose and inulin (OFI) attenuate inflammation in DSS induced colitis. BMC Gastroenterol 6: 31, 2006.
57. Parcellier A, Gurbuxani S, Schmitt E, Solary E, Garrido C. Heat shock proteins, cellular chaperones that modulate mitochondrial cell death pathways. Biochem Biophys Res Commun 304: 505–512, 2003.
58. Patel KK, Stappenbeck TS. Autophagy and intestinal homeostasis. Annu Rev Physiol 75: 241–262, 2013.
59. Petrof EO, Kojima K, Ropeleski MJ, Musch MA, Tao Y, DeSimone C, Chang EB. Probiotics inhibit nuclear factor-kB and induce heat shock proteins in colonic epithelial cells through proteasome inhibition. Gastroenterology 127: 1474–1487, 2004.
60. Petrof EO, Claud EC, Sun J, Abramova T, Guo Y, Waypa TS, He SM, Nakagawa Y, Chang EB. Bacteria-free solution derived from Lactobacillus plantarum inhibits multiple NF-kB pathways and inhibits proteasome function. Inflamm Bowel Dis 15: 1537–1547, 2009.
61. Qiu W, Wu B, Wang X, Buchanan ME, Regueiro MD, Hartman DJ, Schoen RE, Yu J, Zhang L. PUMA-mediated intestinal epithelial apoptosis contributes to ulcerative colitis in humans and mice. J Clin Invest 121: 1722–1732, 2011.
62. Rachmilewitz D, Katakura K, Karmeli F, Hayashi T, Reinus C, Rudensky B, Akira S, Takeda K, Lee J, Takabayashi K, Raz E. Toll-like receptor 9 signaling mediates the anti-inflammatory effects of probiotics in murine experimental colitis. Gastroenterology 126: 520–528, 2004.
63. Randall-Demillo S, Chieppa M, Eri R. Intestinal epithelium and autophagy: partners in gut homeostasis. Front Immunol 4: 301, 2013.
64. Ren H, Musch MW, Kojima K, Boone D, Ma A, Chang EB. Short chain fatty acids induce intestinal epithelial heat shock protein 25 expression in rats and IEC18 cells. Gastroenterology 121: 631–639, 2001.
65. Riedel CU, Foata F, Philippe D, Adolfsson O, Elkmanns BJ, Blum S. Anti-inflammatory effects of bifidobacteria by inhibition of induced NF-kB activation. World J Gastroenterol 12: 3729–3735, 2006.
66. Rubenstein AD, Eisenstein M, Ber Y, Bialik S, Kimchi A. The autophagy protein Atg12 associates with antiapoptotic Bcl-2 family members to promote mitochondrial apoptosis. Mol Cell 9: 698–709, 2011.
67. Saha S, Jing X, Park SY, Wang S, Li X, Gupta D, Dziarski R. Peptidoglycan recognition proteins protect mice from experimental colitis by promoting normal gut flora and preventing induction of interferongamma. Cell Host Microbe 8: 147–162, 2010.
68. Saitoh T, Fujita N, Jang MH, Uematsu S, Yang BG, Satoh T, Omori H, Noda T, Yamamoto N, Komatsu M, Tanaka K, Kawai T, Tsujimura T, Takeuchi O, Yoshimori T, Akira S. Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. Nature 456: 264–268, 2008.
69. Schari M, Rogler G. Inflammatory bowel disease: Dysfunction of autophagy? Dig Dis 30: S12–S19, 2012.
70. Schmidt N, Gonzalez E, Visekruna A, Kuhl AA, Loddenkemper C, Mollenkopf H, Kaufmann SH, Steinhoff U, Joeris T. Targeting the proteasome: Partial inhibition of the proteasome by bortezomib or deletion of the immunosubunit LMP7 attenuates experimental colitis. Gut 59: 896–906, 2010.
71. Segawa S, Fujiya M, Konielli H, Ueno N, Kobayashi N, Shigyo T, Kohgo Y. Probiotic-derived polyphosphate enhances the epithelial barrier function and maintains intestinal homeostasis through integrin-p38 MAPK pathway. PLoS One 6: e23278, 2011.
72. Seidelin JB, Nielsen OH. Epithelial apoptosis: cause or consequence of ulcerative colitis. Scand J Gastroenterol 44: 1429–1434, 2009.
73. Shi CS, Shenderov K, Huang NN, Kabat J, Abu-Asab M, Fitzgerald KA, Kehri JH. Activation of autophagy by inflammatory signals limits IL-1_ production by targeting ubiquitinated inflammasomes for destruction. Nat Immunol 13: 255–623, 2012.
74. Singh SB, Omatkowski W, Vergne I, Naylor J, Delgado M, Robewrts E, Ponpuak M, Master S, Pilli M, White E, Komatsu M, Deretic V. Human IRGM regulates autophagy and its cell autonomous immunity functions through mitochondria. Nat Cell Biol 12: 1154–1165, 2010.
75. Strater J, Wellisch I, Riedl S, Walczak H, Koretz K, Tandara A, Krammer PH, Moller P. CD95(APO-1/Fas)-mediated apoptosis in colon epithelial cells: a possible role in ulcerative colitis. Gastroenterology 113: 160–167, 1997.
76. Tang B, Cai J, Sun L, Li Y, Qu J, Sinder BJ, Wu S. Proteasome inhibitors activate autophagy involving inhibition of PI3K-Akt-mTOR pathway as an anti-oxidant defense in human RPE cells. PLoS One 25: e103364, 2014.
77. Teng X, Xu LF, Zhou P, Sun HW, Sun M. Effects of trefoil peptide 3 on expression of TNF-alpha, TLR4, NH-kappaB in trinitrobenzene sulfonic acid induced colitis mice. Inflammation 32: 120–129, 2009.
78. Tetreault MP, Alrabaa R, McGeehan M, Katz JP. Kruppel like factor 5 protects against murine colitis and activates JAK-STAT signaling in vivo. PLoS One 7: e38338, 2012.
79. Tigno-Aranjuez JT, Asara JM, Abbott DW. Inhibition of RIP2’s tyrosine kinase activity limits NOD2-driven cytokine responses. Genes Dev 24: 2666–2677, 2010.
80. Tsuboi K, Nishitani M, Takakura A, Imai Y, Komatsu M, Kawashima H. Autophagy protects against colitis by the maintenance of normal gut microflora and secretion of mucus. J Biol Chem 290: 20511–20526, 2015.
81. Tuohy KM, Probert HM, Smejkal CW, Gibson GR. Using probiotics and prebiotics to improve gut health. Drug Discov Today 8: 692–700, 2003.
82. Williams JA, Hou Y, Ni HM, Ding XX. Role of intracellular calcium in proteasome inhibitor induced endoplasmic reticulum stress, autophagy, and cell death. Pharm Res 30: 2279–2289, 2013.
83. Wittkopf N, Gunther C, Martini E, Waldner M, Amann KU, Neurath MF, Becker C. Lack of intestinal epithelial Atg7 affects Paneth cell granule formation but does not compromise immune homeostasis in the gut. Clin Dev Immunol 2012: 278059, 2012.
84. Yanaba K, Asano Y, Tada Y, Sugaya M, Kadono T, Sato S. Proteasome inhibitor bortezomib ameliorates intestinal injury in mice. PLoS One 7: e34587, 2012.
85. Yan F, Cao H, Cover TL, Washington MK, Shi Y, Liu L, Chaturvedi R, Peek RM Jr, Wilson KT, Polk DB. Colon-specific delivery of a probiotic-derived soluble protein ameliorates intestinal inflammation in mice through and EGFR-dependent mechanism. J Clin Invest 121: 2242–2253, 2011.
86. Yousefi S, Perozzo R, Schmid I, Ziemiecki A, Schaffner T, Scapozza L, Brunner T, Simon HU. Calpain mediated cleavage of Atg5 switches autophagy to apoptosis. Nat Cell Biol 8: 1124–1132, 2006.
87. Zakostelska Z, Kverka M, Klimesova K, Klimesova K, Rossmann P, Mrazek J, Kopecny J, Hornova M, Srutkova D, Hudcovic T, Ridl J, Tlaskalova-Hogenova H. Lysate of Lactobacillus casei DN-114 001 ameliorates colitis by strengthening the gut barrier function and changing the gut microenvironment. PLoS One 6: e27961, 2011.
88. Zhu K, Dunner K, McConkey DF. Proteasome inhibitors activate autophagy as a cytoprotective response in human prostate cancer cells. Oncogene 21: 4523–4462, 2010.
89. Zhu X, Messer JS, Wang Y, Lin F, Cham C, Chang J, Billiar TR, Lotze MT, Boone DL, Chang EB. Cytosolic HMGB1 controls the cellular autophagy/apoptosis checkpoint during inflammation. J Clin Invest 125: 1098–1110, 2015.