The pseudokinase MLKL mediates programmed hepatocellular necrosis independently of RIPK3 during hepatitis

Journal of Clinical Investigation

Volumn 126, Issue 11, 2016, Pages 4346-4360

  Günther, Claudia ^a   He, Gui Wei ^a   Kremer, Andreas E ^a   Murphy, James M ^b,c   Petrie, Emma J ^b,c   Amann, Kerstin ^a   Vandenabeele, Peter ^d,e   Linkermann, Andreas ^f   Poremba, Christopher ^g   Schleicher, Ulrike ^h   Dewitz, Christin ^f   Krautwald, Stefan ^f   Neurath, Markus F ^a   Becker, Christoph ^a   Wirtz, Stefan ^a  

^a UNIVERSITY OF ERLANGEN NUREMBERG   (Germany)

^b WALTER AND ELIZA HALL INSTITUTE OF MEDICAL RESEARCH   (Australia)

^c UNIVERSITY OF MELBOURNE   (Australia)

^d GHENT UNIVERSITY   (Belgium)

^e DEPARTMENT OF PLANT SYSTEMS BIOLOGY   (Belgium)

^f UNIVERSITY HOSPITAL SCHLESWIG HOLSTEIN   (Germany)

^g University Hospital Schleswig Holstein ^*  (Germany)

^h UNIVERSITY HOSPITAL ERLANGEN   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

ALANINE AMINOTRANSFERASE; ALBUMIN; ASPARTATE AMINOTRANSFERASE; CASPASE 3; GAMMA INTERFERON; LACTATE DEHYDROGENASE; MIXED LINEAGE KINASE; MIXED LINEAGE KINASE DOMAIN LIKE PROTEIN; PROTEIN KINASE; RECEPTOR INTERACTING PROTEIN KINASE 3; STAT1 PROTEIN; UNCLASSIFIED DRUG; IFNG PROTEIN, HUMAN; IFNG PROTEIN, MOUSE; MLKL PROTEIN, HUMAN; MLKL PROTEIN, MOUSE; RECEPTOR INTERACTING PROTEIN SERINE THREONINE KINASE; RIPK3 PROTEIN, HUMAN; RIPK3 PROTEIN, MOUSE; STAT1 PROTEIN, HUMAN; STAT1 PROTEIN, MOUSE;

ALANINE AMINOTRANSFERASE BLOOD LEVEL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; ASPARTATE AMINOTRANSFERASE BLOOD LEVEL; AUTOIMMUNE HEPATITIS; CONTROLLED STUDY; CYTOTOXICITY; HUMAN; HUMAN CELL; LIVER NECROSIS; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; ANIMAL; ENZYMOLOGY; GENETICS; KNOCKOUT MOUSE; LIVER CELL; METABOLISM; NECROSIS; PATHOLOGY;

ANIMALS; HEPATITIS, AUTOIMMUNE; HEPATOCYTES; HUMANS; INTERFERON-GAMMA; MICE; MICE, KNOCKOUT; NECROSIS; PROTEIN KINASES; RECEPTOR-INTERACTING PROTEIN SERINE-THREONINE KINASES; STAT1 TRANSCRIPTION FACTOR;

EID: 84994683550     PISSN: 00219738     EISSN: 15588238     Source Type: Journal    
DOI: 10.1172/JCI87545     Document Type: Article

References (61)

1. Vandenabeele P, Galluzzi L, Vanden Berghe T, Kroemer G. Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol. 2010;11(10):700-714
2. Degterev A, et al. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat Chem Biol. 2005;1(2):112-119
3. Vercammen D, et al. Dual signaling of the Fas receptor: initiation of both apoptotic and necrotic cell death pathways. J Exp Med. 1998;188(5):919-930
4. Zhang H, Zhou X, McQuade T, Li J, Chan FK, Zhang J. Functional complementation between FADD and RIP1 in embryos and lymphocytes. Nature. 2011;471(7338):373-376
5. Kaiser WJ, et al. RIP3 mediates the embryonic lethality of caspase-8-deficient mice. Nature. 2011;471(7338):368-372
6. Oberst A, et al. Catalytic activity of the caspase-8-FLIP(L) complex inhibits RIPK3-dependent necrosis. Nature. 2011;471(7338):363-367
7. Sun L, et al. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell. 2012;148(1-2):213-227
8. Gunther C, et al. Caspase-8 regulates TNF-α-induced epithelial necroptosis and terminal ileitis. Nature. 2011;477(7364):335-339
9. Feoktistova M, et al. cIAPs block Ripoptosome formation, a RIP1/caspase-8 containing intracellular cell death complex differentially regulated by cFLIP isoforms. Mol Cell. 2011;43(3):449-463
10. Cai Z, et al. Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis. Nat Cell Biol. 2014;16(1):55-65
11. Hildebrand JM, et al. Activation of the pseudokinase MLKL unleashes the four-helix bundle domain to induce membrane localization and necroptotic cell death. Proc Natl Acad Sci U S A. 2014;111(42):15072-15077
12. Bonnet MC, et al. The adaptor protein FADD protects epidermal keratinocytes from necroptosis in vivo and prevents skin inflammation. Immunity. 2011;35(4):572-582
13. Ma X, et al. The oncogenic microRNA miR-21 promotes regulated necrosis in mice. Nat Commun. 2015;6:7151
14. Linkermann A, et al. Two independent pathways of regulated necrosis mediate ischemia-reperfusion injury. Proc Natl Acad Sci U S A. 2013;110(29):12024-12029
15. Luedde T, Kaplowitz N, Schwabe RF. Cell death and cell death responses in liver disease: mechanisms and clinical relevance. Gastroenterology. 2014;147(4):765-783.e4
16. Wang H, et al. Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3. Mol Cell. 2014;54(1):133-146
17. Ramachandran A, McGill MR, Xie Y, Ni HM, Ding WX, Jaeschke H. Receptor interacting protein kinase 3 is a critical early mediator of acetaminophen-induced hepatocyte necrosis in mice. Hepatology. 2013;58(6):2099-2108
18. Takemoto K, et al. Necrostatin-1 protects against reactive oxygen species (ROS)-induced hepatotoxicity in acetaminophen-induced acute liver failure. FEBS Open Bio. 2014;4:777-787
19. Dara L, et al. Receptor interacting protein kinase 1 mediates murine acetaminophen toxicity independent of the necrosome and not through necroptosis. Hepatology. 2015;62(6):1847-1857
20. Roychowdhury S, McMullen MR, Pisano SG, Liu X, Nagy LE. Absence of receptor interacting protein kinase 3 prevents ethanol-induced liver injury. Hepatology. 2013;57(5):1773-1783
21. Deutsch M, et al. Divergent effects of RIP1 or RIP3 blockade in murine models of acute liver injury. Cell Death Dis. 2015;6:e1759
22. Manns MP, Lohse AW, Vergani D. Autoimmune hepatitis-Update 2015. J Hepatol. 2015;62(1 Suppl): S100-S111
23. Hussain MJ, Mustafa A, Gallati H, Mowat AP, Mieli-Vergani G, Vergani D. Cellular expression of tumour necrosis factor-alpha and interferon-gamma in the liver biopsies of children with chronic liver disease. J Hepatol. 1994;21(5):816-821
24. Kusters S, Gantner F, Kunstle G, Tiegs G. Interferon gamma plays a critical role in T cell-dependent liver injury in mice initiated by concanavalin A. Gastroenterology. 1996;111(2):462-471
25. Horras CJ, Lamb CL, Mitchell KA. Regulation of hepatocyte fate by interferon-and gamma;. Cytokine Growth Factor Rev. 2011;22(1):35-43
26. Siebler J, et al. A key pathogenic role for the STAT1/T-bet signaling pathway in T-cellmediated liver inflammation. Hepatology. 2003;38(6):1573-1580
27. Sun R, et al. STAT1 contributes to dsRNA inhibition of liver regeneration after partial hepatectomy in mice. Hepatology. 2006;44(4):955-966
28. Tanzer MC, et al. Necroptosis signalling is tuned by phosphorylation of MLKL residues outside the pseudokinase domain activation loop. Biochem J. 2015;471(2):255-265
29. Tiegs G, Hentschel J, Wendel A. A T cell-dependent experimental liver injury in mice inducible by concanavalin A. J Clin Invest. 1992;90(1):196-203
30. Heymann F, Hamesch K, Weiskirchen R, Tacke F. The concanavalin A model of acute hepatitis in mice. Lab Anim. 2015;49(1 Suppl):12-20
31. Murphy JM, et al. The pseudokinase MLKL mediates necroptosis via a molecular switch mechanism. Immunity. 2013;39(3):443-453
32. Degterev A, et al. Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat Chem Biol. 2008;4(5):313-321
33. Dillon CP, et al. RIPK1 blocks early postnatal lethality mediated by caspase-8 and RIPK3. Cell. 2014;157(5):1189-1202
34. Rickard JA, et al. RIPK1 regulates RIPK3-MLKLdriven systemic inflammation and emergency hematopoiesis. Cell. 2014;157(5):1175-1188
35. Kaiser WJ, et al. RIP1 suppresses innate immune necrotic as well as apoptotic cell death during mammalian parturition. Proc Natl Acad Sci U S A. 2014;111(21):7753-7758
36. Duprez L, et al. RIP kinase-dependent necrosis drives lethal systemic inflammatory response syndrome. Immunity. 2011;35(6):908-918
37. Rodriguez DA, et al. Characterization of RIPK3-mediated phosphorylation of the activation loop of MLKL during necroptosis. Cell Death Differ. 2016;23(1):76-88
38. Pine R, Canova A, Schindler C. Tyrosine phosphorylated p91 binds to a single element in the ISGF2/ IRF-1 promoter to mediate induction by IFN alpha and IFN gamma, and is likely to autoregulate the p91 gene. EMBO J. 1994;13(1):158-167
39. Maeda S, Chang L, Li ZW, Luo JL, Leffert H, Karin M. IKKbeta is required for prevention of apoptosis mediated by cell-bound but not by circulating TNFalpha. Immunity. 2003;19(5):725-737
40. Kusters S, et al. In vivo evidence for a functional role of both tumor necrosis factor (TNF) receptors and transmembrane TNF in experimental hepatitis. Eur J Immunol. 1997;27(11):2870-2875
41. Chen X, et al. Translocation of mixed lineage kinase domain-like protein to plasma membrane leads to necrotic cell death. Cell Res. 2014;24(1):105-121
42. Dondelinger Y, et al. MLKL compromises plasma membrane integrity by binding to phosphatidylinositol phosphates. Cell Rep. 2014;7(4):971-981
43. Kang YJ, et al. Regulation of NKT cell-mediated immune responses to tumours and liver inflammation by mitochondrial PGAM5-Drp1 signalling. Nat Commun. 2015;6:8371
44. Newton K, Manning G. Necroptosis and inflammation. Annu Rev Biochem. 2016;85:743-763
45. Dondelinger Y, Hulpiau P, Saeys Y, Bertrand MJ, Vandenabeele P. An evolutionary perspective on the necroptotic pathway [published online ahead of print June 28, 2016]. Trends Cell Biol. doi: 10.1016/j.tcb.2016.06.004
46. Tanzer MC, et al. Evolutionary divergence of the necroptosis effector MLKL. Cell Death Differ. 2016;23(7):1185-1197
47. McGill MR, Sharpe MR, Williams CD, Taha M, Curry SC, Jaeschke H. The mechanism underlying acetaminophen-induced hepatotoxicity in humans and mice involves mitochondrial damage and nuclear DNA fragmentation. J Clin Invest. 2012;122(4):1574-1583
48. Vinken M, et al. Primary hepatocytes and their cultures in liver apoptosis research. Arch Toxicol. 2014;88(2):199-212
49. Rodriguez DA, et al. Characterization of RIPK3-mediated phosphorylation of the activation loop of MLKL during necroptosis. Cell Death Differ. 2016;23(1):76-88
50. McComb S, et al. Type-I interferon signaling through ISGF3 complex is required for sustained Rip3 activation and necroptosis in macrophages. Proc Natl Acad Sci U S A. 2014;111(31):E3206-E3213
51. Dusheiko G. Side effects of alpha interferon in chronic hepatitis C. Hepatology. 1997; 26(3 Suppl 1):112S-121S
52. Garcia-Buey L, et al. Latent autoimmune hepatitis triggered during interferon therapy in patients with chronic hepatitis C. Gastroenterology. 1995;108(6):1770-1777
53. Newton K, Sun X, Dixit VM. Kinase RIP3 is dispensable for normal NF-kappa Bs, signaling by the B-cell and T-cell receptors, tumor necrosis factor receptor 1, and Toll-like receptors 2 and 4. Mol Cell Biol. 2004;24(4):1464-1469
54. Bajt ML, Knight TR, Lemasters JJ, Jaeschke H. Acetaminophen-induced oxidant stress and cell injury in cultured mouse hepatocytes: protection by N-acetyl cysteine. Toxicol Sci. 2004;80(2):343-349
55. McHedlidze T, et al. Interleukin-33-dependent innate lymphoid cells mediate hepatic fibrosis. Immunity. 2013;39(2):357-371
56. Murphy JM, et al. A robust methodology to subclassify pseudokinases based on their nucleotide-binding properties. Biochem J. 2014;457(2):323-334
57. Babon JJ, Murphy JM. In vitro JAK kinase activity and inhibition assays. Methods Mol Biol. 2013;967:39-55
58. Cook WD, et al. RIPK1-and RIPK3-induced cell death mode is determined by target availability. Cell Death Differ. 2014;21(10):1600-1612
59. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Autoimmune hepatitis. J Hepatol. 2015;63(4):971-1004
60. Cartharius K, et al. MatInspector and beyond: promoter analysis based on transcription factor binding sites. Bioinformatics. 2005;21(13):2933-2942
61. Marinescu VD, Kohane IS, Riva A. MAPPER: a search engine for the computational identification of putative transcription factor binding sites in multiple genomes. BMC Bioinformatics. 2005;6:79