Differential phosphatidylinositol-3-kinase-Akt-mTOR activation by Semliki Forest and Chikungunya viruses is dependent on nsP3 and connected to replication complex internalization

Journal of Virology

Volumn 89, Issue 22, 2015, Pages 11420-11437

  Thaa, Bastian ^a   Biasiotto, Roberta ^a   Eng, Kai ^a   Neuvonen, Maarit ^b   Götte, Benjamin ^a   Rheinemann, Lara ^a   Mutso, Margit ^c   Utt, Age ^c   Varghese, Finny ^d   Balistreri, Giuseppe ^b   Merits, Andres ^c   Ahola, Tero ^d   McInerney, Gerald M ^a  

^a KAROLINSKA INSTITUTE   (Sweden)

^b UNIVERSITY OF HELSINKI   (Finland)

^c UNIVERSITY OF TARTU   (Estonia)

^d UNIVERSITY OF HELSINKI   (Finland)

Author keywords

[No Author keywords available]

Indexed keywords

MAMMALIAN TARGET OF RAPAMYCIN; NONSTRUCTURAL PROTEIN 3; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN KINASE B; WORTMANNIN; 1-(4-(4-PROPIONYLPIPERAZIN-1-YL)-3-(TRIFLUOROMETHYL)PHENYL)-9-(QUINOLIN-3-YL)BENZO(H)(1,6)NAPHTHYRIDIN-2(1H)-ONE; ANDROSTANE DERIVATIVE; MTOR PROTEIN, HUMAN; NAPHTHYRIDINE DERIVATIVE; NSP3 PROTEIN, SEMLIKI FOREST VIRUS; RAPAMYCIN; RNA BINDING PROTEIN; TARGET OF RAPAMYCIN KINASE; VIRAL PROTEIN;

ALPHAVIRUS INFECTION; ANIMAL CELL; ARTICLE; CARBOXY TERMINAL SEQUENCE; CELL MEMBRANE; CHIKUNGUNYA; CHIKUNGUNYA VIRUS; CONTROLLED STUDY; ENZYME ACTIVATION; ENZYME PHOSPHORYLATION; HUMAN; HUMAN CELL; INTERNALIZATION; MEMBRANE BINDING; MOUSE; NONHUMAN; NUTRITIONAL DEFICIENCY; PHENOTYPE; PRIORITY JOURNAL; PROTEIN DEPLETION; PROTEIN DOMAIN; PROTEIN EXPRESSION; PROTEIN PROTEIN INTERACTION; SEMLIKI FOREST VIRUS; SEMLIKI FOREST VIRUS INFECTION; VIRUS CELL INTERACTION; VIRUS REPLICATION; ANIMAL; ANTAGONISTS AND INHIBITORS; DRUG EFFECTS; GENETICS; HAMSTER; METABOLISM; PHOSPHORYLATION; PROTEIN TERTIARY STRUCTURE; SIGNAL TRANSDUCTION; TUMOR CELL LINE; VIROLOGY; VIRUS ENTRY;

ALPHAVIRUS INFECTIONS; ANDROSTADIENES; ANIMALS; CELL LINE, TUMOR; CHIKUNGUNYA VIRUS; CRICETINAE; ENZYME ACTIVATION; HUMANS; MICE; NAPHTHYRIDINES; PHOSPHATIDYLINOSITOL 3-KINASE; PHOSPHORYLATION; PROTEIN STRUCTURE, TERTIARY; PROTO-ONCOGENE PROTEINS C-AKT; RNA-BINDING PROTEINS; SEMLIKI FOREST VIRUS; SIGNAL TRANSDUCTION; SIROLIMUS; TOR SERINE-THREONINE KINASES; VIRAL NONSTRUCTURAL PROTEINS; VIRUS INTERNALIZATION; VIRUS REPLICATION;

EID: 84945959691     PISSN: 0022538X     EISSN: 10985514     Source Type: Journal    
DOI: 10.1128/JVI.01579-15     Document Type: Article

References (62)

1. Atkins GJ, Sheahan BJ, Liljeström P. 1999. The molecular pathogenesis of Semliki Forest virus: a model virus made useful? J Gen Virol 80:2287-2297. http://dx.doi.org/10.1099/0022-1317-80-9-2287.
2. Karlsson GB, Liljeström P. 2004. Delivery and expression of heterologous genes in mammalian cells using self-replicating alphavirus vectors. Methods Mol Biol 246:543-557.
3. Ljungberg K, Liljeström P. 2015. Self-replicating alphavirus RNA vaccines. Expert Rev Vaccines 14:177-194. http://dx.doi.org/10.1586/14760584.2015.965690.
4. Quetglas JI, Ruiz-Guillen M, Aranda A, Casales E, Bezunartea J, Smerdou C. 2010. Alphavirus vectors for cancer therapy. Virus Res 153:179-196. http://dx.doi.org/10.1016/j.virusres.2010.07.027.
5. Karabatsos N. 1975. Antigenic relationships of group A arboviruses by plaque reduction neutralization testing. Am J Trop Med Hyg 24:527-532.
6. Jose J, Snyder JE, Kuhn RJ. 2009. A structural and functional perspective of alphavirus replication and assembly. Future Microbiol 4:837-856. http://dx.doi.org/10.2217/fmb.09.59.
7. Rupp JC, Sokoloski KJ, Gebhart NN, Hardy RW. 24 July 2015. Alphavirus RNA synthesis and nonstructural protein functions. J Gen Virol http://dx.doi.org/10.1099/jgv.0.000249.
8. Malet H, Coutard B, Jamal S, Dutartre H, Papageorgiou N, Neuvonen M, Ahola T, Forrester N, Gould EA, Lafitte D, Ferron F, Lescar J, Gorbalenya AE, de Lamballerie X, Canard B. 2009. The crystal structures of chikungunya and Venezuelan equine encephalitis virus nsP3 macro domains define a conserved adenosine binding pocket. J Virol 83:6534-6545. http://dx.doi.org/10.1128/JVI.00189-09.
9. Neuvonen M, Ahola T. 2009. Differential activities of cellular and viral macro domain proteins in binding of ADP-ribose metabolites. J Mol Biol 385:212-225. http://dx.doi.org/10.1016/j.jmb.2008.10.045.
10. Shin G, Yost SA, Miller MT, Elrod EJ, Grakoui A, Marcotrigiano J. 2012. Structural and functional insights into alphavirus polyprotein processing and pathogenesis. Proc Natl Acad Sci U S A 109:16534-16539. http://dx.doi.org/10.1073/pnas.1210418109.
11. McInerney GM. 23 June 2015. FGDF motif regulation of stress granule formation. DNA Cell Biol 34:557-560. http://dx.doi.org/10.1089/dna.2015.2957.
12. Panas MD, Ahola T, McInerney GM. 2014. The C-terminal repeat domains of nsP3 from the Old World alphaviruses bind directly to G3BP. J Virol 88:5888-5893. http://dx.doi.org/10.1128/JVI.00439-14.
13. Panas MD, Varjak M, Lulla A, Eng KE, Merits A, Karlsson Hedestam GB, McInerney GM. 2012. Sequestration of G3BP coupled with efficient translation inhibits stress granules in Semliki Forest virus infection. Mol Biol Cell 23:4701-4712. http://dx.doi.org/10.1091/mbc. E12-08-0619.
14. Panas MD, Schulte T, Thaa B, Sandalova T, Kedersha N, Achour A, McInerney GM. 2015. Viral and cellular proteins containing FGDF motifs bind G3BP to block stress granule formation. PLoS Pathog 11:e1004659. http://dx.doi.org/10.1371/journal.ppat.1004659.
15. Kedersha N, Ivanov P, Anderson P. 2013. Stress granules and cell signaling: more than just a passing phase? Trends Biochem Sci 38:494-506. http://dx.doi.org/10.1016/j.tibs.2013.07.004.
16. Spuul P, Balistreri G, Kääriäinen L, Ahola T. 2010. Phosphatidylinositol 3-kinase-, actin-, and microtubule-dependent transport of Semliki Forest virus replication complexes from the plasma membrane to modified lysosomes. J Virol 84:7543-7557. http://dx.doi.org/10.1128/JVI.00477-10.
17. Manning BD, Cantley LC. 2007. AKT/PKB signaling: navigating downstream. Cell 129:1261-1274. http://dx.doi.org/10.1016/j.cell.2007.06.009.
18. Laplante M, Sabatini DM. 2012. mTOR signaling in growth control and disease. Cell 149:274-293. http://dx.doi.org/10.1016/j.cell.2012.03.017.
19. Dunn EF, Connor JH. 2012. HijAkt: The PI3K/Akt pathway in virus replication and pathogenesis. Prog Mol Biol Transl Sci 106:223-250. http://dx.doi.org/10.1016/B978-0-12-396456-4.00002-X.
20. Cooray S. 2004. The pivotal role of phosphatidylinositol 3-kinase-Akt signal transduction in virus survival. J Gen Virol 85:1065-1076. http://dx.doi.org/10.1099/vir.0.19771-0.
21. Diehl N, Schaal H. 2013. Make yourself at home: viral hijacking of the PI3K/Akt signaling pathway. Viruses 5:3192-3212. http://dx.doi.org/10.3390/v5123192.
22. Buchkovich NJ, Yu Y, Zampieri CA, Alwine JC. 2008. The TORrid affairs of viruses: effects of mammalian DNA viruses on the PI3K-Akt mTOR signalling pathway. Nat Rev Microbiol 6:266-275. http://dx.doi.org/10.1038/nrmicro1855.
23. Ehrhardt C, Marjuki H, WolffT, Nürnberg B, Planz O, Pleschka S, Ludwig S. 2006. Bivalent role of the phosphatidylinositol-3-kinase (PI3K) during influenza virus infection and host cell defence. Cell Microbiol 8:1336-1348. http://dx.doi.org/10.1111/j.1462-5822.2006.00713.x.
24. Dunn EF, Connor JH. 2011. Dominant inhibition of Akt/protein kinase B signaling by the matrix protein of a negative-strand RNA virus. J Virol 85:422-431. http://dx.doi.org/10.1128/JVI.01671-10.
25. Mohankumar V, Dhanushkodi NR, Raju R. 2011. Sindbis virus replication, is insensitive to rapamycin and torin1, and suppresses Akt/mTOR pathway late during infection in HEK cells. Biochem Biophys Res Commun 406:262-267. http://dx.doi.org/10.1016/j.bbrc.2011.02.030.
26. Patel RK, Hardy RW. 2012. Role for the phosphatidylinositol 3-kinase-Akt-TOR pathway during sindbis virus replication in arthropods. J Virol 86:3595-3604. http://dx.doi.org/10.1128/JVI.06625-11.
27. Das I, Basantray I, Mamidi P, Nayak TK, Pratheek BM, Chattopadhyay S, Chattopadhyay S. 2014. Heat shock protein 90 positively regulates chikungunya virus replication by stabilizing viral non-structural protein nsP2 during infection. PLoS One 9:e100531. http://dx.doi.org/10.1371/journal.pone.0100531.
28. Salonen A, Vasiljeva L, Merits A, Magden J, Jokitalo E, Kääriäinen L. 2003. Properly folded nonstructural polyprotein directs the Semliki Forest virus replication complex to the endosomal compartment. J Virol 77: 1691-1702. http://dx.doi.org/10.1128/JVI.77.3.1691-1702.2003.
29. Liljeström P, Lusa S, Huylebroeck D, GaroffH. 1991. In vitro mutagenesis of a full-length cDNA clone of Semliki Forest virus: the small 6,000-molecular-weight membrane protein modulates virus release. J Virol 65: 4107-4113.
30. Sjöberg EM, Suomalainen M, GaroffH. 1994. A significantly improved Semliki Forest virus expression system based on translation enhancer segments from the viral capsid gene. Biotechnology 12:1127-1131. http://dx.doi.org/10.1038/nbt1194-1127.
31. Smerdou C, Liljeström P. 1999. Two-helper RNA system for production of recombinant Semliki Forest virus particles. J Virol 73:1092-1098.
32. Ulper L, Sarand I, Rausalu K, Merits A. 2008. Construction, properties, and potential application of infectious plasmids containing Semliki Forest virus full-length cDNA with an inserted intron. J Virol Methods 148:265-270. http://dx.doi.org/10.1016/j.jviromet.2007.10.007.
33. Vihinen H, Ahola T, Tuittila M, Merits A, Kääriäinen L. 2001. Elimination of phosphorylation sites of Semliki Forest virus replicase protein nsP3. J Biol Chem 276:5745-5752. http://dx.doi.org/10.1074/jbc. M006077200.
34. Neuvonen M, Kazlauskas A, Martikainen M, Hinkkanen A, Ahola T, Saksela K. 2011. SH3 domain-mediated recruitment of host cell amphiphysins by alphavirus nsP3 promotes viral RNA replication. PLoS Pathog 7:e1002383. http://dx.doi.org/10.1371/journal.ppat.1002383.
35. Varjak M, Žusinaite E, Merits A. 2010. Novel functions of the alphavirus nonstructural protein nsP3 C-terminal region. J Virol 84:2352-2364. http://dx.doi.org/10.1128/JVI.01540-09.
36. Vihinen H, Saarinen J. 2000. Phosphorylation site analysis of Semliki Forest virus nonstructural protein 3. J Biol Chem 275:27775-27783.
37. Pohjala L, Utt A, Varjak M, Lulla A, Merits A, Ahola T, Tammela P. 2011. Inhibitors of alphavirus entry and replication identified with a stable chikungunya replicon cell line and virus-based assays. PLoS One 6:e28923. http://dx.doi.org/10.1371/journal.pone.0028923.
38. Hallengärd D, Kakoulidou M, Lulla A, Kümmerer BM, Johansson DX, Mutso M, Lulla V, Fazakerley JK, Roques P, Le Grand R, Merits A, Liljeström P. 2014. Novel attenuated chikungunya vaccine candidates elicit protective immunity in C57BL/6 mice. J Virol 88:2858-2866. http://dx.doi.org/10.1128/JVI.03453-13.
39. Spuul P, Balistreri G, Hellström K, Golubtsov AV, Jokitalo E, Ahola T. 2011. Assembly of alphavirus replication complexes from RNA and protein components in a novel trans-replication system in mammalian cells. J Virol 85:4739-4751. http://dx.doi.org/10.1128/JVI.00085-11.
40. Gorchakov R, Frolova E, Williams BR, Rice CM, Frolov I. 2004. PKR-dependent and-independent mechanisms are involved in translational shutoffduring Sindbis virus infection. J Virol 78:8455-8467. http://dx.doi.org/10.1128/JVI.78.16.8455-8467.2004.
41. Cristea IM, Carroll JW, Rout MP, Rice CM, Chait BT, MacDonald MR. 2006. Tracking and elucidating alphavirus-host protein interactions. J Biol Chem 281:30269-30278. http://dx.doi.org/10.1074/jbc. M603980200.
42. Kujala P, Rikkonen M, Ahola T, Kelve M, Saarma M, Kääriäinen L. 1997. Monoclonal antibodies specific for Semliki Forest virus replicase protein nsP2. J Gen Virol 78:343-351. http://dx.doi.org/10.1099/0022-1317-78-2-343.
43. Tamberg N, Lulla V, Fragkoudis R, Lulla A, Fazakerley JK, Merits A. 2007. Insertion of EGFP into the replicase gene of Semliki Forest virus results in a novel, genetically stable marker virus. J Gen Virol 88:1225-1230. http://dx.doi.org/10.1099/vir.0.82436-0.
44. Scholte FE, Tas A, Albulescu IC, Žusinaite E, Merits A, Snijder EJ, van Hemert MJ. 2015. Stress granule components G3BP1 and G3BP2 play a proviral role early in chikungunya virus replication. J Virol 89:4457-4469. http://dx.doi.org/10.1128/JVI.03612-14.
45. Utt A, Das PK, Varjak M, Lulla V, Lulla A, Merits A. 2015. Mutations conferring a noncytotoxic phenotype on chikungunya virus replicons compromise enzymatic properties of nonstructural protein 2. J Virol 89: 3145-3162. http://dx.doi.org/10.1128/JVI.03213-14.
46. Peränen J, Laakkonen P, Hyvonen M, Kääriäinen L. 1995. The alphavirus replicase protein nsP1 is membrane-associated and has affinity to endocytic organelles. Virology 208:610-620. http://dx.doi.org/10.1006/viro.1995.1192.
47. Downward J. 1998. Mechanisms and consequences of activation of protein kinase B/Akt. Curr Opin Cell Biol 10:262-267. http://dx.doi.org/10.1016/S0955-0674(98)80149-X.
48. Resh MD. 1999. Fatty acylation of proteins: new insights into membrane targeting of myristoylated and palmitoylated proteins. Biochim Biophys Acta 1451:1-16. http://dx.doi.org/10.1016/S0167-4889(99)00075-0.
49. Gorchakov R, Garmashova N, Frolova E, Frolov I. 2008. Different types of nsP3-containing protein complexes in Sindbis virus-infected cells. J Virol 82:10088-10101. http://dx.doi.org/10.1128/JVI.01011-08.
50. Ahola T, Kujala P, Tuittila M, Blom T, Laakkonen P, Hinkkanen A, Auvinen P. 2000. Effects of palmitoylation of replicase protein nsP1 on alphavirus infection. J Virol 74:6725-6733. http://dx.doi.org/10.1128/JVI.74.15.6725-6733.2000.
51. Spuul P, Salonen A, Merits A, Jokitalo E, Kääriäinen L, Ahola T. 2007. Role of the amphipathic peptide of Semliki Forest virus replicase protein nsP1 in membrane association and virus replication. J Virol 81:872-883. http://dx.doi.org/10.1128/JVI.01785-06.
52. Frolova E, Gorchakov R, Garmashova N, Atasheva S, Vergara LA, Frolov I. 2006. Formation of nsP3-specific protein complexes during Sindbis virus replication. J Virol 80:4122-4134. http://dx.doi.org/10.1128/JVI.80.8.4122-4134.2006.
53. Shin YK, Li Y, Liu Q, Anderson DH, Babiuk LA, Zhou Y. 2007. SH3 binding motif 1 in influenza A virus NS1 protein is essential for PI3K/Akt signaling pathway activation. J Virol 81:12730-12739. http://dx.doi.org/10.1128/JVI.01427-07.
54. Hale BG, Jackson D, Chen YH, Lamb RA, Randall RE. 2006. Influenza A virus NS1 protein binds p85β and activates phosphatidylinositol-3-kinase signaling. Proc Natl Acad SciUSA103:14194-14199. http://dx.doi.org/10.1073/pnas.0606109103.
55. Peränen J, Takkinen K, Kalkkinen N, Kääriäinen L. 1988. Semliki Forest virus-specific non-structural protein nsP3 is a phosphoprotein. J Gen Virol 69:2165-2178. http://dx.doi.org/10.1099/0022-1317-69-9-2165.
56. Li GP, LaStarza MW, Hardy WR, Strauss JH, Rice CM. 1990. Phosphorylation of Sindbis virus nsP3 in vivo and in vitro. Virology 179:416-427. http://dx.doi.org/10.1016/0042-6822(90)90310-N.
57. Frolova EI, Gorchakov R, Pereboeva L, Atasheva S, Frolov I. 2010. Functional Sindbis virus replicative complexes are formed at the plasma membrane. J Virol 84:11679-11695. http://dx.doi.org/10.1128/JVI.01441-10.
58. Galbraith SE, Sheahan BJ, Atkins GJ. 2006. Deletions in the hypervariable domain of the nsP3 gene attenuate Semliki Forest virus virulence. The J Gen Virol 87:937-947. http://dx.doi.org/10.1099/vir.0.81406-0.
59. Ferguson MC, Saul S, Fragkoudis R, Weisheit S, Cox J, Patabendige A, Sherwood K, Watson M, Merits A, Fazakerley JK. 2015. The ability of the encephalitic arbovirus Semliki Forest virus to cross the blood brain barrier is determined by the charge of the E2 glycoprotein. J Virol 89:7536-7549. http://dx.doi.org/10.1128/JVI.03645-14.
60. Tuittila M, Hinkkanen AE. 2003. Amino acid mutations in the replicase protein nsP3 of Semliki Forest virus cumulatively affect neurovirulence. J Gen Virol 84:1525-1533. http://dx.doi.org/10.1099/vir.0.18936-0.
61. Saul S, Ferguson MC, Cordonin C, Fragkoudis R, Ool M, Tamberg N, Sherwood K, Fazakerley JK, Merits A. 26 August 2015. Differences in processing determinants of non-structural polyprotein and in the sequence of non-structural protein 3 affect neurovirulence of Semliki Forest virus. J Virol 89:11030-11045. http://dx.doi.org/10.1128/JVI.01186-15.
62. Akhrymuk I, Kulemzin SV, Frolova EI. 2012. Evasion of the innate immune response: the Old World alphavirus nsP2 protein induces rapid degradation of Rpb1, a catalytic subunit of RNA polymerase II. J Virol 86:7180-7191. http://dx.doi.org/10.1128/JVI.00541-12.