Protease 3C of hepatitis A virus induces vacuolization of lysosomal/endosomal organelles and caspase-independent cell death

BMC Cell Biology

Sergey V Kostrov¹  Olga G Leonova²  Marina P Roschina³  Alexey A Komissarov³  Nataliya A Lunina³  Ilya V Demidyuk³  Andrey V Shubin³ 

[1] National Research Center “Kurchatov Institute”, Moscow 123182, Russia;Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119992, Russia;Laboratory of Protein Engineering, Institute of Molecular Genetics, Russian Academy of Science, Moscow 123182, Russia

关键词: Caspase-independent cell death;    Cytoplasmic vacuolization;    Hepatitis A virus;    3C protease;   

Others  :  1137095
DOI  :  10.1186/s12860-015-0050-z

【 摘 要 】

Background

3C proteases, the main proteases of picornaviruses, play the key role in viral life cycle by processing polyproteins. In addition, 3C proteases digest certain host cell proteins to suppress antiviral defense, transcription, and translation. The activity of 3C proteases per se induces host cell death, which makes them critical factors of viral cytotoxicity. To date, cytotoxic effects have been studied for several 3C proteases, all of which induce apoptosis. This study for the first time describes the cytotoxic effect of 3C protease of human hepatitis A virus (3Cpro), the only proteolytic enzyme of the virus.

Results

Individual expression of 3Cpro induced catalytic activity-dependent cell death, which was not abrogated by the pan-caspase inhibitor (z-VAD-fmk) and was not accompanied by phosphatidylserine externalization in contrast to other picornaviral 3C proteases. The cell survival was also not affected by the inhibitors of cysteine proteases (z-FA-fmk) and RIP1 kinase (necrostatin-1), critical enzymes involved in non-apoptotic cell death. A substantial fraction of dying cells demonstrated numerous non-acidic cytoplasmic vacuoles with not previously described features and originating from several types of endosomal/lysosomal organelles. The lysosomal protein Lamp1 and GTPases Rab5, Rab7, Rab9, and Rab11 were associated with the vacuolar membranes. The vacuolization was completely blocked by the vacuolar ATPase inhibitor (bafilomycin A1) and did not depend on the activity of the principal factors of endosomal transport, GTPases Rab5 and Rab7, as well as on autophagy and macropinocytosis.

Conclusions

3Cpro, apart from other picornaviral 3C proteases, induces caspase-independent cell death, accompanying by cytoplasmic vacuolization. 3Cpro-induced vacuoles have unique properties and are formed from several organelle types of the endosomal/lysosomal compartment. The data obtained demonstrate previously undocumented morphological characters of the 3Cpro-induced cell death, which can reflect unknown aspects of the human hepatitis A virus-host cell interaction.

【 授权许可】

   
2015 Shubin et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Figure 7.

Figure 8.

Figure 9.

【 参考文献 】

• [1]Lin J-Y, Chen T-C, Weng K-F, Chang S-C, Chen L-L, Shin S-R: Viral and host proteins involved in picornavirus life cycle. J Biomed Sci 1996, 16:103.
• [2]Clark ME, Hämmerle T, Wimmer E, Dasgupta A: Poliovirus proteinase 3C converts an active form of transcription factor IIIC to an inactive form: a mechanism for inhibition of host cell polymerase III transcription by poliovirus. EMBO J 1991, 10:2941-2947.
• [3]Clark ME, Lieberman PM, Berk AJ, Dasgupta A: Direct cleavage of human TATA-binding protein by poliovirus protease 3C in vivo and in vitro. Mol Cell Biol 1993, 13:1232-1237.
• [4]Yalamanchili P, Datta U, Dasgupta A: Inhibition of host cell transcription by poliovirus: cleavage of transcription factor CREB by poliovirus-encoded protease 3Cpro. J Virol 1997, 71:1220-1226.
• [5]Belsham GJ, McInerney GM, Ross-Smith N: Foot-and-mouth disease virus 3C protease induces cleavage of translation initiation factors eIF4A and eIF4G within infected cells. J Virol 2000, 74:272-280.
• [6]Weidman MK, Yalamanchili P, Ng B, Tsai W, Dasgupta A: Poliovirus 3C protease-mediated degradation of transcriptional activator p53 requires a cellular activity. Virology 2001, 291:260-271.
• [7]Kuyumcu-Martinez NM, Joachims M, Lloyd RE: Efficient cleavage of ribosome-associated poly(A)-binding protein by enterovirus 3C protease. J Virol 2002, 76:2062-2074.
• [8]Amineva SP, Aminev AG, Palmenberg AC, Gern JE: Rhinovirus 3C protease precursors 3CD and 3CD’ localize to the nuclei of infected cells. J Gen Virol 2004, 85:2969-2979.
• [9]Kuyumcu-Martinez NM, Eden MEV, Younan P, Lloyd RE: Cleavage of Poly(A)-Binding Protein by Poliovirus 3C Protease Inhibits Host Cell Translation: a Novel Mechanism for Host Translation Shutoff. Mol Cell Biol 2004, 24:1779-1790.
• [10]Weng K-F, Li M-L, Hung C-T, Shih S-R: Enterovirus 71 3C protease cleaves a novel target CstF-64 and inhibits cellular polyadenylation. PLoS Pathog 2009, 5:e1000593.
• [11]Kobayashi M, Arias C, GaRabedian A, Palmenberg AC, Mohr I: Site-specific cleavage of the host poly(A) binding protein by the encephalomyocarditis virus 3C proteinase stimulates viral replication. J Virol 2012, 86:10686-10694.
• [12]Falk MM, Grigera PR, Bergmann IE, Zibert A, Multhaup G, Beck E: Foot-and-mouth disease virus protease 3C induces specific proteolytic cleavage of host cell histone H3. J Virol 1990, 64:748-756.
• [13]Joachims M, Harris KS, Etchison D: Poliovirus protease 3C mediates cleavage of microtubule-associated protein 4. Virology 1995, 211:451-461.
• [14]Armer H, Moffat K, Wileman T, Belsham GJ, Jackson T, Duprex WP, et al.: Foot-and-mouth disease virus, but not bovine enterovirus, targets the host cell cytoskeleton via the nonstructural protein 3Cpro. J Virol 2008, 82:10556-10566.
• [15]Neznanov N, Chumakov KM, Neznanova L, Almasan A, Banerjee AK, Gudkov AV: Proteolytic cleavage of the p65-RelA subunit of NF-kappaB during poliovirus infection. J Biol Chem 2005, 280:24153-24158.
• [16]Mukherjee A, Morosky SA, Delorme-Axford E, Dybdahl-Sissoko N, Oberste MS, Wang T, et al.: The coxsackievirus B 3C protease cleaves MAVS and TRIF to attenuate host type I interferon and apoptotic signaling. PLoS Pathog 2011, 7:e1001311.
• [17]Lei X, Xiao X, Xue Q, Jin Q, He B, Wang J: Cleavage of interferon regulatory factor 7 by enterovirus 71 3C suppresses cellular responses. J Virol 2013, 87:1690-1698.
• [18]Li M-L, Hsu T-A, Chen T-C, Chang S-C, Lee J-C, Chen C-C, et al.: The 3C protease activity of enterovirus 71 induces human neural cell apoptosis. Virology 2002, 293:386-395.
• [19]Calandria C, Irurzun A, Barco A, Carrasco L: Individual expression of poliovirus 2Apro and 3Cpro induces activation of caspase-3 and PARP cleavage in HeLa cells. Virus Res 2004, 104:39-49.
• [20]Chau DHW, Yuan J, Zhang H, Cheung P, Lim T, Liu Z, et al.: Coxsackievirus B3 proteases 2A and 3C induce apoptotic cell death through mitochondrial injury and cleavage of eIF4GI but not DAP5/p97/NAT1. Apoptosis 2006, 12:513-524.
• [21]Zhang B, Morace G, Gauss-Müller V, Kusov Y: Poly(A) binding protein, C-terminally truncated by the hepatitis A virus proteinase 3C, inhibits viral translation. Nucleic Acids Res 2007, 35:5975-5984.
• [22]Zhang B, Seitz S, Kusov Y, Zell R, Gauss-Müller V: RNA interaction and cleavage of poly(C)-binding protein 2 by hepatitis A virus protease. Biochem Biophys Res Commun 2007, 364:725-730.
• [23]Yang Y, Liang Y, Qu L, Chen Z, Yi M, Li K, et al.: Disruption of innate immunity due to mitochondrial targeting of a picornaviral protease precursor. Proc Natl Acad Sci USA 2007, 104:7253-7258.
• [24]Qu L, Feng Z, Yamane D, Liang Y, Lanford RE, Li K, et al.: Disruption of TLR3 Signaling Due to Cleavage of TRIF by the Hepatitis A Virus Protease-Polymerase Processing Intermediate, 3CD. PLoS Pathog 2011, 7:e1002169.
• [25]Peters H, Kusov YY, Meyer S, Benie AJ, Bäuml E, Wolff M, et al.: Hepatitis A virus proteinase 3C binding to viral RNA: correlation with substrate binding and enzyme dimerization. Biochem J 2005, 385:363-370.
• [26]Johnson LV, Walsh ML, Chen LB: Localization of mitochondria in living cells with rhodamine 123. Proc Natl Acad Sci USA 1980, 77:990-994.
• [27]Galluzzi L, Vitale I, Abrams JM, Alnemri ES, Baehrecke EH, Blagosklonny MV, et al.: Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death. Cell Death Differ 2012, 19:107-120.
• [28]Guicciardi ME, Leist M, Gores GJ: Lysosomes in cell death. Oncogene 2004, 23:2881-2890.
• [29]Stoka V, Turk V, Turk B: Do lysosomes induce cell death? IUBMB Life 2006, 58:493-494.
• [30]Han W, Xie J, Li L, Liu Z, Hu X: Necrostatin-1 reverts shikonin-induced necroptosis to apoptosis. Apoptosis 2009, 14:674-686.
• [31]Song J, Jang HJ, Lee YA, Kim KA, Lee SK, Shin MH: Reactive oxygen species-dependent necroptosis in Jurkat T cells induced by pathogenic free-living Naegleria fowleri. Parasite Immunology 2011, 33:390-400.
• [32]Kaznelson DW, Bruun S, Monrad A, Gjerløv S, Birk J, Röpke C, et al.: Simultaneous human papilloma virus type 16 E7 and cdk inhibitor p21 expression induces apoptosis and cathepsin B activation. Virology 2004, 320:301-312.
• [33]Yamashima T: Ca2+-dependent proteases in ischemic neuronal death. Cell Calcium 2004, 36:285-293.
• [34]Harwood SM, Yaqoob MM, Allen DA: Caspase and calpain function in cell death: bridging the gap between apoptosis and necrosis. Ann Clin Biochem 2005, 42:415-431.
• [35]McCall K: Genetic control of necrosis - another type of programmed cell death. Curr Opin Cell Biol 2010, 22:882-888.
• [36]Schrader K, Huai J, Jöckel L, Oberle C, Borner C: Non-caspase proteases: triggers or amplifiers of apoptosis? Cell Mol Life Sci 2010, 67:1607-1618.
• [37]Repnik U, Stoka V, Turk V, Turk B: Lysosomes and lysosomal cathepsins in cell death. Biochim Biophys Acta 1824, 2012:22-33.
• [38]Wolf BB, Goldstein JC, Stennicke HR, Beere H, Amarante-Mendes GP, Salvesen GS, et al.: Calpain functions in a caspase-independent manner to promote apoptosis-like events during platelet activation. Blood 1999, 94:1683-1692.
• [39]Schotte P, Declercq W, Van Huffel S, Vandenabeele P, Beyaert R: Non-specific effects of methyl ketone peptide inhibitors of caspases. FEBS Lett 1999, 442:117-121.
• [40]Holler N, Zaru R, Micheau O, Thome M, Attinger A, Valitutti S, et al.: Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat Immunol 2000, 1:489-495.
• [41]Degterev A, Hitomi J, Germscheid M, Ch’en IL, Korkina O, Teng X, et al.: Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat Chem Biol 2008, 4:313-321.
• [42]Rizzuto R, Brini M, Pizzo P, Murgia M, Pozzan T: Chimeric green fluorescent protein as a tool for visualizing subcellular organelles in living cells. Curr Biol 1995, 5:635-642.
• [43]Klee M, Pimentel-Muiños FX: Bcl-X(L) specifically activates Bak to induce swelling and restructuring of the endoplasmic reticulum. J Cell Biol 2005, 168:723-734.
• [44]Cook NR, Row PE, Davidson HW: Lysosome associated membrane protein 1 (Lamp1) traffics directly from the TGN to early endosomes. Traffic 2004, 5:685-699.
• [45]Blümer J, Rey J, Dehmelt L, Mazel T, Wu Y-W, Bastianes P, et al.: RabGEFs are a major determinant for specific Rab membrane targeting. J Cell Biol 2013, 200:287-300.
• [46]Schwartz SL, Cao C, Pylypenko O, Rak A, Wandinger-Ness A: Rab GTPases at a glance. J Cell Sci 2007, 120:3905-3910.
• [47]Stenmark H: Rab GTPases as coordinators of vesicle traffic. Nat Rev Mol Cell Biol 2009, 10:513-525.
• [48]Bucci C, Parton RG, Mather IH, Stunnenberg H, Simons K, Hoflack B, et al.: The small GTPase Rab5 functions as a regulatory factor in the early endocytic pathway. Cell 1992, 70:715-728.
• [49]Spinosa MR, Progida C, De Luca A, Colucci AMR, Alifano P, Bucci C: Functional characterization of Rab7 mutant proteins associated with Charcot-Marie-Tooth type 2B disease. J Neurosci 2008, 28:1640-1648.
• [50]Papini E, Satin B, Bucci C, de Bernard M, Telford JL, Manetti R, et al.: The small GTP binding protein Rab7 is essential for cellular vacuolation induced by Helicobacter pylori cytotoxin. EMBO J 1997, 16:15-24.
• [51]Li X-Z, Sui C-Y, Chen Q, Chen X-P, Zhang H: Zhou X-p: Promotion of autophagy at the maturation step by IL-6 is associated with the sustained mitogen-activated protein kinase/extracellular signal-regulated kinase activity. Mol Cell Biochem 2013, 380:219-227.
• [52]Cagnol S, Chambard J-C: ERK and cell death: Mechanisms of ERK-induced cell death – apoptosis, autophagy and senescence. FEBS J 2010, 277:2-21.
• [53]Blommaart EF, Krause U, Schellens JP, Vreeling-Sindelárová H, Meijer AJ: The Phosphatidylinositol 3-Kinase Inhibitors Wortmannin and LY294002 Inhibit Autophagy in Isolated Rat Hepatocytes. Eur J Biochem 1997, 243:240-246.
• [54]Petiot A, Ogier-Denis E, Blommaart EF, Meijer AJ, Codogno P: Distinct classes of phosphatidylinositol 3′-kinases are involved in signaling pathways that control macroautophagy in HT-29 cells. J Biol Chem 2000, 275:992-998.
• [55]Jahreiss L, Menzies FM, Rubinsztein DC: The itinerary of autophagosomes: from peripheral formation to kiss-and-run fusion with lysosomes. Traffic 2008, 9:574-587.
• [56]Mousavi SA, Kjeken R, Berg TO, Seglen PO, Berg T, Brech A: Effects of inhibitors of the vacuolar proton pump on hepatic heterophagy and autophagy. Biochim Biophys Acta 2001, 1510:243-257.
• [57]Clague MJ, Urbé S, Aniento F, Gruenberg J: Vacuolar ATPase activity is required for endosomal carrier vesicle formation. J Biol Chem 1994, 269:21-24.
• [58]Luzio JP, Pryor PR, Bright NA: Lysosomes: fusion and function. Nat Rev Mol Cell Biol 2007, 8:622-632.
• [59]Overmeyer JH, Kaul A, Johnson EE, Maltese WA: Active ras triggers death in glioblastoma cells through hyperstimulation of macropinocytosis. Mol Cancer Res 2008, 6:965-977.
• [60]Bhanot H, Young AM, Overmeyer JH, Maltese WA: Induction of nonapoptotic cell death by activated Ras requires inverse regulation of Rac1 and Arf6. Mol Cancer Res 2010, 8:1358-1374.
• [61]Grimmer S, van Deurs B, Sandvig K: Membrane ruffling and macropinocytosis in A431 cells require cholesterol. J Cell Sci 2002, 115:2953-2962.
• [62]Buenz EJ, Howe CL: Picornaviruses and cell death. Trends Microbiol 2006, 14:28-36.
• [63]Collins JA, Schandi CA, Young KK, Vesely J, Willingham MC: Major DNA fragmentation is a late event in apoptosis. J Histochem Cytochem 1997, 45:923-934.
• [64]Maeno E, Ishizaki Y, Kanaseki T, Hazama A, Okada Y: Normotonic cell shrinkage because of disordered volume regulation is an early prerequisite to apoptosis. Proc Natl Acad Sci USA 2000, 97:9487-9492.
• [65]Pradelli LA, Bénéteau M, Ricci J-E: Mitochondrial control of caspase-dependent and -independent cell death. Cell Mol Life Sci 2010, 67:1589-1597.
• [66]Johnson VL, Ko SC, Holmstrom TH, Eriksson JE, Chow SC: Effector caspases are dispensable for the early nuclear morphological changes during chemical-induced apoptosis. J Cell Sci 2000, 113:2941-2953.
• [67]Kroemer G, Martin SJ: Caspase-independent cell death. Nat Med 2005, 11:725-730.
• [68]Constantinou C, Papas KA, Constantinou AI: Caspase-independent pathways of programmed cell death: the unraveling of new targets of cancer therapy? Curr Cancer Drug Targets 2009, 9:717-728.
• [69]Hirabayashi M, Inoue K, Tanaka K, Nakadate K, Ohsawa Y, Kamei Y, et al.: VCP/p97 in abnormal protein aggregates, cytoplasmic vacuoles, and cell death, phenotypes relevant to neurodegeneration. Cell Death Differ 2001, 8:977-984.
• [70]Kourie JI: Prion channel proteins and their role in vacuolation and neurodegenerative diseases. Eur Biophys J 2002, 31:409-416.
• [71]Manfredi G, Xu Z: Mitochondrial dysfunction and its role in motor neuron degeneration in ALS. Mitochondrion 2005, 5:77-87.
• [72]Vigliano CA, Meckert PMC, Diez M, Favaloro LE, Cortés C, Fazzi L, et al.: Cardiomyocyte hypertrophy, oncosis, and autophagic vacuolization predict mortality in idiopathic dilated cardiomyopathy with advanced heart failure. J Am Coll Cardiol 2011, 57:1523-1531.
• [73]Kar R, Singha PK, Venkatachalam MA, Saikumar P: A novel role for MAP1 LC3 in nonautophagic cytoplasmic vacuolation death of cancer cells. Oncogene 2009, 28:2556-2568.
• [74]Vesa J, Su H, Watts GD, Krause S, Walter MC, Martin B, et al.: Valosin containing protein associated inclusion body myopathy: abnormal vacuolization, autophagy and cell fusion in myoblasts. Neuromuscul Disord 2009, 19:766-772.
• [75]Watanabe E, Muenzer JT, Hawkins WG, Davis CG, Dixon DJ, McDunn JE, et al.: Sepsis induces extensive autophagic vacuolization in hepatocytes: a clinical and laboratory-based study. Lab Invest 2009, 89:549-561.
• [76]Alcalá S, Klee M, Fernández J, Fleischer A, Pimentel-Muiños FX: A high-throughput screening for mammalian cell death effectors identifies the mitochondrial phosphate carrier as a regulator of cytochrome c release. Oncogene 2008, 27:44-54.
• [77]Yuan J, Kroemer G: Alternative cell death mechanisms in development and beyond. Genes Dev 2010, 24:2592-2602.
• [78]Singha PK, Pandeswara S, Venkatachalam MA, Saikumar P: Manumycin A inhibits triple-negative breast cancer growth through LC3-mediated cytoplasmic vacuolation death. Cell Death Dis 2013, 4:e457.
• [79]Sperandio S, de Belle I, Bredesen DE: An alternative, nonapoptotic form of programmed cell death. Proc Natl Acad Sci USA 2000, 97:14376-14381.
• [80]Vandenabeele P, Galluzzi L, Vanden Berghe T, Kroemer G: Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol 2010, 11:700-714.
• [81]Høyer-Hansen M, Bastholm L, Mathiasen IS, Elling F, Jäättelä M: Vitamin D analog EB1089 triggers dramatic lysosomal changes and Beclin 1-mediated autophagic cell death. Cell Death Differ 2005, 12:1297-1309.
• [82]Hansen K, Wagner B, Hamel W, Schweizer M, Haag F, Westphal M, et al.: Autophagic cell death induced by TrkA receptor activation in human glioblastoma cells. J Neurochem 2007, 103:259-275.
• [83]Funakoshi T, Aki T, Unuma K, Uemura K: Lysosome vacuolation disrupts the completion of autophagy during norephedrine exposure in SH-SY5Y human neuroblastoma cells. Brain Res 2013, 1490:9-22.
• [84]Corcelle E, Nebout M, Bekri S, Gauthier N, Hofman P, Poujeol P, et al.: Disruption of autophagy at the maturation step by the carcinogen lindane is associated with the sustained mitogen-activated protein kinase/extracellular signal-regulated kinase activity. Cancer Res 2006, 66:6861-6870.
• [85]Klionsky DJ, Elazar Z, Seglen PO, Rubinsztein DC: Does bafilomycin A1 block the fusion of autophagosomes with lysosomes? Autophagy 2008, 4:849-950.
• [86]Barbero P, Bittova L, Pfeffer SR: Visualization of Rab9-mediated vesicle transport from endosomes to the trans-Golgi in living cells. J Cell Biol 2002, 156:511-518.
• [87]Humphries WH, Szymanski CJ, Payne CK: Endo-lysosomal vesicles positive for Rab7 and Lamp1 are terminal vesicles for the transport of dextran. PLoS ONE 2011, 6:e26626.
• [88]Vonderheit A, Helenius A: Rab7 associates with early endosomes to mediate sorting and transport of Semliki forest virus to late endosomes. PLoS Biol 2005, 3:e233.
• [89]Trischler M, Stoorvogel W, Ullrich O: Biochemical analysis of distinct Rab5- and Rab11-positive endosomes along the transferrin pathway. J Cell Sci 1999, 112:4773-4783.
• [90]Sönnichsen B, De Renzis S, Nielsen E, Rietdorf J, Zerial M: Distinct membrane domains on endosomes in the recycling pathway visualized by multicolor imaging of Rab4, Rab5, and Rab11. J Cell Biol 2000, 149:901-914.
• [91]Hutagalung AH, Novick PJ: Role of Rab GTPases in membrane traffic and cell physiology. Physiol Rev 2011, 91:119-149.
• [92]Johnson EE, Overmeyer JH, Gunning WT, Maltese WA: Gene silencing reveals a specific function of hVps34 phosphatidylinositol 3-kinase in late versus early endosomes. J Cell Sci 2006, 119:1219-1232.
• [93]Jefferies HBJ, Cooke FT, Jat P, Boucheron C, Koizumi T, Hayakawa M, et al.: A selective PIKfyve inhibitor blocks PtdIns(3,5)P2 production and disrupts endomembrane transport and retroviral budding. EMBO Rep 2008, 9:164-170.
• [94]Cuesta-Geijo MA, Galindo I, Hernáez B, Quetglas JI, Dalmau-Mena I, Alonso C: Endosomal Maturation, Rab7 GTPase and Phosphoinositides in African Swine Fever Virus Entry. PLoS ONE 2012, 7:e48853.
• [95]Nagahama M, Itohayashi Y, Hara H, Higashihara M, Fukatani Y, Takagishi T, et al.: Cellular vacuolation induced by Clostridium perfringens epsilon-toxin. FEBS J 2011, 278:3395-3407.
• [96]Johnson C, Kannan TR, Baseman JB: Cellular Vacuoles Induced by Mycoplasma pneumoniae CARDS Toxin Originate from Rab9-Associated Compartments. PLoS ONE 2011, 6:e22877.
• [97]Stenmark H, Parton RG, Steele-Mortimer O, Lütcke A, Gruenberg J, Zerial M: Inhibition of Rab5 GTPase activity stimulates membrane fusion in endocytosis. EMBO J 1994, 13:1287-1296.
• [98]Vitelli R, Santillo M, Lattero D, Chiariello M, Bifulco M, Bruni CB, et al.: Role of the small GTPase Rab7 in the late endocytic pathway. J Biol Chem 1997, 272:4391-4397.
• [99]Overmeyer JH, Young AM, Bhanot H, Maltese WA: A chalcone-related small molecule that induces methuosis, a novel form of non-apoptotic cell death, in glioblastoma cells. Mol Cancer 2011, 10:69.
• [100]Brack K, Frings W, Dotzauer A, Vallbracht A: A cytopathogenic, apoptosis-inducing variant of hepatitis A virus. J Virol 1998, 72:3370-3376.
• [101]Kulka M, Chen A, Ngo D, Bhattacharya SS, Cebula TA, Goswami BB: The cytopathic 18f strain of Hepatitis A virus induces RNA degradation in FrhK4 cells. Arch Virol 2003, 148:1275-1300.
• [102]Goswami BB, Kulka M, Ngo D, Cebula TA: Apoptosis induced by a cytopathic hepatitis A virus is dependent on caspase activation following ribosomal RNA degradation but occurs in the absence of 2′-5′ oligoadenylate synthetase. Antiviral Res 2004, 63:153-166.
• [103]Agol VI, Belov GA, Bienz K, Egger D, Kolesnikova MS, Raikhlin NT, et al.: Two types of death of poliovirus-infected cells: caspase involvement in the apoptosis but not cytopathic effect. Virology 1998, 252:343-353.
• [104]Agol VI, Belov GA, Bienz K, Egger D, Kolesnikova MS, Romanova LI, et al.: Competing death programs in poliovirus-infected cells: commitment switch in the middle of the infectious cycle. J Virol 2000, 74:5534-5541.
• [105]Chu JJH, Ng ML: The mechanism of cell death during West Nile virus infection is dependent on initial infectious dose. J Gen Virol 2003, 84:3305-3314.
• [106]Tamm I: Cell injury with viruses. Am J Pathol 1975, 81:163-178.
• [107]Agol VI: Cytopathic effects: virus-modulated manifestations of innate immunity? Trends Microbiol 2012, 20:570-576.
• [108]Dales S, Eggers HJ, Tamm I, Palade GE: Electron microscopic study of the formation of poliovirus. Virology 1965, 26:379-389.
• [109]Asher LV, Binn LN, Marchwicki RH: Demonstration of hepatitis A virus in cell culture by electron microscopy with immunoperoxidase staining. J Virol Methods 1987, 15:323-328.
• [110]Shimizu YK, Shikata T, Beninger PR, Sata M, Setoyama H, Abe H, et al.: Detection of hepatitis A antigen in human liver. Infect Immun 1982, 36:320-324.
• [111]Gosert R, Egger D, Bienz K: A cytopathic and a cell culture adapted hepatitis A virus strain differ in cell killing but not in intracellular membrane rearrangements. Virology 2000, 266:157-169.
• [112]Martin A, Lemon SM: Hepatitis A virus: from discovery to vaccines. Hepatology 2006, 43(Suppl 1):S164-S172.
• [113]Teterina NL, Bienz K, Egger D, Gorbalenya AE, Ehrenfeld E: Induction of intracellular membrane rearrangements by HAV proteins 2C and 2BC. Virology 1997, 237:66-77.
• [114]Hildt E, Saher G, Bruss V, Hofschneider PH: The hepatitis B virus large surface protein (LHBs) is a transcriptional activator. Virology 1996, 225:235-239.
• [115]Foo N-C, Ahn BY, Ma X, Hyun W, Yen TSB: Cellular vacuolization and apoptosis induced by hepatitis B virus large surface protein. Hepatology 2002, 36:1400-1407.
• [116]DesGroseillers L, Barrette M, Jolicoeur P: Physical mapping of the paralysis-inducing determinant of a wild mouse ecotropic neurotropic retrovirus. J Virol 1984, 52:356-363.
• [117]Takase-Yoden S, Watanabe R: Unique sequence and lesional tropism of a new variant of neuropathogenic friend murine leukemia virus. Virology 1997, 233:411-422.
• [118]Takase-Yoden S, Watanabe R: A 0.3-kb fragment containing the R-U5-5′ leader sequence is essential for the induction of spongiform neurodegeneration by A8 murine leukemia virus. Virology 2005, 336:1-10.
• [119]Murata H, Peden K, Lewis AM: Identification of a mutation in the SV40 capsid protein VP1 that influences plaque morphology, vacuolization, and receptor usage. Virology 2008, 370:343-351.
• [120]Krawczyk E, Suprynowicz FA, Liu X, Dai Y, Hartmann DP, Hanover J, et al.: Koilocytosis: a cooperative interaction between the human papillomavirus E5 and E6 oncoproteins. Am J Pathol 2008, 173:682-688.
• [121]Krawczyk E, Hanover JA, Schlegel R, Suprynowicz FA: Karyopherin beta3: a new cellular target for the HPV-16 E5 oncoprotein. Biochem Biophys Res Commun 2008, 371:684-688.
• [122]Krawczyk E, Suprynowicz FA, Hebert JD, Kamonjoh CM, Schlegel R: The human papillomavirus type 16 E5 oncoprotein translocates calpactin I to the perinuclear region. J Virol 2011, 85:10968-10975.
• [123]Sanderson CM, Parkinson JE, Hollinshead M, Smith GL: Overexpression of the vaccinia virus A38L integral membrane protein promotes Ca2+ influx into infected cells. J Virol 1996, 70:905-914.
• [124]Allaire M, Chernaia MM, Malcolm BA, James MN: Picornaviral 3C cysteine proteinases have a fold similar to chymotrypsin-like serine proteinases. Nature 1994, 369:72-76.
• [125]Love RA, Parge HE, Wickersham JA, Hostomsky Z, Habuka N, Moomaw EW, et al.: The crystal structure of hepatitis C virus NS3 proteinase reveals a trypsin-like fold and a structural zinc binding site. Cell 1996, 87:331-342.
• [126]Steffan A, Marianneau P, Caussin-Schwemling C, Royer C, Schmitt C, Jaeck D, et al.: Ultrastructural observations in hepatitis C virus-infected lymphoid cells. Microbes Infect 2001, 3:193-202.
• [127]Zargar S, Wani TA, Jain SK: Morphological changes in vero cells postinfection with dengue virus type-2. Microsc Res Tech 2011, 74:314-319.
• [128]Ramanathan MP, Chambers JA, Pankhong P, Chattergoon M, Attatippaholkun W, Dang K, et al.: Host cell killing by the West Nile Virus NS2B-NS3 proteolytic complex: NS3 alone is sufficient to recruit caspase-8-based apoptotic pathway. Virology 2006, 345:56-72.
• [129]Shafee N, AbuBakar S: Dengue virus type 2 NS3 protease and NS2B-NS3 protease precursor induce apoptosis. J Gen Virol 2003, 84:2191-2195.
• [130]Egger D, Wölk B, Gosert R, Bianchi L, Blum HE, Moradpour D, et al.: Expression of hepatitis C virus proteins induces distinct membrane alterations including a candidate viral replication complex. J Virol 2002, 76:5974-5984.
• [131]Birk AV, Dubovi EJ, Cohen-Gould L, Donis R, Szeto HH: Cytoplasmic vacuolization responses to cytopathic bovine viral diarrhoea virus. Virus Res 2008, 132:76-85.
• [132]Mendez E, Ruggli N, Collett MS, Rice CM: Infectious bovine viral diarrhea virus (strain NADL) RNA from stable cDNA clones: a cellular insert determines NS3 production and viral cytopathogenicity. J Virol 1998, 72:4737-4745.
• [133]Qi F, Ridpath JF, Berry ES: Insertion of a bovine SMT3B gene in NS4B and duplication of NS3 in a bovine viral diarrhea virus genome correlate with the cytopathogenicity of the virus. Virus Res 1998, 57:1-9.
• [134]Choudhury A, Dominguez M, Puri V, Sharma DK, Narita K, Wheatley CL, et al.: Rab proteins mediate Golgi transport of caveola-internalized glycosphingolipids and correct lipid trafficking in Niemann-Pick C cells. J Clin Invest 2002, 109:1541-1550.
• [135]Sharma DK, Choudhury A, Singh RD, Wheatley CL, Marks DL, Pagano RE: Glycosphingolipids internalized via caveolar-related endocytosis rapidly merge with the clathrin pathway in early endosomes and form microdomains for recycling. J Biol Chem 2003, 278:7564-7572.
• [136]Kabeya Y, Mizushima N, Yamamoto A, Oshitani-Okamoto S, Ohsumi Y, Yoshimori T: LC3, GABARAP and GATE16 localize to autophagosomal membrane depending on form-II formation. J Cell Sci 2004, 117:2805-2812.
• [137]Hoppe AD, Swanson JA: Cdc42, Rac1, and Rac2 display distinct patterns of activation during phagocytosis. Mol Biol Cell 2004, 15:3509-3519.
• [138]Sverdlov SD, Tsarev SA, Markova SV, Vasilenko SK: Cloning and expression of hepatitis A virus genome in E. coli cells. Mol Gen Microbiol Virol 1987, 2:129-133.