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Gene Review

SENP8  -  SUMO/sentrin specific peptidase family...

Homo sapiens

Synonyms: DEN1, Deneddylase-1, FKSG8, HsT17512, NEDD8-specific protease 1, ...
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Disease relevance of SENP8

  • Inhibition studies and mutagenesis indicate that NEDP1 is a cysteine protease with sequence similarities to SUMO-specific proteases and the class of viral proteases typified by the adenovirus protease [1].
  • Sense and antisense genome sequences from La Crosse virus (LAC) (a member of the Bunyaviridae) and dengue viruses serotypes 1 to 4 (DEN-1 to DEN-4) (members of the Flaviviridae) were expressed in mosquito cells from double-subgenomic and replicon vectors based on Sindbis virus (a member of the Togaviridae) [2].
  • A split decomposition analysis of dengue (DEN) virus gene sequences revealed extensive networked evolution, indicative of recombination, among DEN-1 strains but not within serotypes DEN-2, DEN-3, or DEN-4 [3].
  • To ascertain if dsRNA-triggered RNAi is present in mosquito cells, we used Aedes albopictus C6/36 cells, and to investigate the feasibility of blocking viral gene expression and replication, we used two mosquito-borne viruses, Semliki Forest virus (SFV) and the serotype 1 dengue virus (DEN1) [4].
  • We constructed chimeric dengue type 2/type 1 (DEN-2/DEN-1) viruses containing the nonstructural genes of DEN-2 16681 virus or its vaccine derivative, strain PDK-53, and the structural genes (encoding capsid protein, premembrane protein, and envelope glycoprotein) of DEN-1 16007 virus or its vaccine derivative, strain PDK-13 [5].

High impact information on SENP8

  • This reveals that NEDP1 is a cysteine protease of the Ulp family [6].
  • Co-expression of NEDP1, a cysteine protease that specifically cleaves NEDD8 conjugates, was shown to deneddylate TAp73 [7].
  • This protein, DEN1, is a 221-amino acid thiol protease that is encoded by an open reading frame previously annotated as SENP8 [8].
  • Here we report the introduction of these same mutational changes into the analogous region of an infectious DNA derived from the genome of a human-virulent dengue serotype 1 virus (DEN1), strain Western Pacific (DEN1WP) [9].
  • We demonstrate that dsRNA can specifically inhibit transgene expression in C6/36 cells from both plasmid and SFV replicons and can significantly modify the kinetics of DEN1 RNA and virus replication [4].

Biological context of SENP8

  • Recombinant human DEN1 shows significant specificity for Nedd8 and catalyzes the hydrolysis of Nedd8 amidomethylcoumarin with a Km of 51 nm and a kcat of7s-1 [8].
  • The resulting DEN1 mutant (DEN1mutF) exhibited a host range-restricted phenotype similar to that of DEN2mutF virus [9].
  • Taking a divergence of 6% between the nucleotide sequences as the cut-off value, three genotype groups were defined for DEN-1 viruses, whereas only one was observed for DEN-4 viruses [10].
  • Maximum nucleotide sequence variation was 6.9% and 4.9% for DEN-1 and DEN-4 viruses, respectively [10].
  • Genetic variation between geographically and temporally distinct isolates of dengue-1 (DEN-1) and dengue-4 (DEN-4) viruses was investigated [10].

Anatomical context of SENP8

  • We analyzed the CD4+ T-lymphocyte responses to dengue, West Nile, and yellow fever viruses 4 months after immunization of a volunteer with an experimental live-attenuated dengue virus type 1 vaccine (DEN-1 45AZ5) [11].
  • The higher susceptibility of Vero cells to DEN-1 correlated with greater binding affinity of DEN-1 to these cells [12].
  • We analysed the binding and infectivity of dengue virus serotype 1 (DEN-1) for the human hepatoma cell line HepG2 in comparison with the simian kidney cell line Vero [12].
  • Using a serotype-specific monoclonal antibody (MAb) of dengue virus type 1 (DEN-1), 15F3-1, we identified the B-cell epitope of DEN-1 from a random peptide library displayed on phage [13].
  • In the first successful experiment, DEN-1 virus was recovered on postinoculation day (PID) 24 from blood, spleen, thymus, and lung tissues of one of eight hu-PBL-SCID mice [14].

Associations of SENP8 with chemical compounds

  • NEDP1, a highly conserved cysteine protease that deNEDDylates Cullins [1].
  • Bacterially expressed NEDP1 is capable of processing NEDD8 in vitro to expose the diglycine motif required for conjugation and can deconjugate NEDD8 from modified substrates [1].
  • We now report the X-ray structures of the human Nedd8-specific protease, Den1, in a complex with the inhibitor Nedd8 aldehyde, thus revealing a model for the tetrahedral transition state intermediate generated during proteolysis [15].
  • Chimeric viruses containing the nonstructural genes of DEN-2 PDK-53 virus and the structural genes of the parental DEN-1 16007 virus retained the attenuation markers of small plaque size and temperature sensitivity in LLC-MK(2) cells, less efficient replication in C6/36 cells, and attenuation for mice [5].
  • All serotypes of DEN viruses, DEN1 to DEN4, reacted with nLc(4)Cer, and the non-reducing terminal disaccharide residue Galbeta1-4GlcNAcbeta1- was found to be a critical determinant for the binding of DEN2 [16].

Other interactions of SENP8


Analytical, diagnostic and therapeutic context of SENP8

  • The higher sensitivity of 16-4 in detecting DEN-1 was found with both IF and flow cytometry [21].
  • Based on these observations, our DEN-1 epitope-based serologic test could be useful in laboratory viral diagnosis and in understanding the pathogenesis of DEN-1 [13].
  • To find fast and reliable methods to diagnose dengue in the early phase of the disease, patient acute-phase sera were investigated for the presence of dengue-specific immunoglobulin M (IgM) antibodies by enzyme-linked immunosorbent assay (ELISA) and also for dengue serotype (DEN-1 to DEN-4)-specific RNA by different PCR assays [22].
  • The identity of all viral isolates was confirmed by an immunofluorescence antibody assay using DEN-1 monoclonal antibody [14].
  • To understand the molecular epidemiology of this virus, 15 strains of DEN-1 isolated during 1987-1991 and 1994-1995, including 11 epidemic strains, two sporadic strains, and two imported strains have been studied [23].


  1. NEDP1, a highly conserved cysteine protease that deNEDDylates Cullins. Mendoza, H.M., Shen, L.N., Botting, C., Lewis, A., Chen, J., Ink, B., Hay, R.T. J. Biol. Chem. (2003) [Pubmed]
  2. Molecular strategies for interrupting arthropod-borne virus transmission by mosquitoes. Blair, C.D., Adelman, Z.N., Olson, K.E. Clin. Microbiol. Rev. (2000) [Pubmed]
  3. Phylogenetic evidence for recombination in dengue virus. Holmes, E.C., Worobey, M., Rambaut, A. Mol. Biol. Evol. (1999) [Pubmed]
  4. Inhibition of viral gene expression and replication in mosquito cells by dsRNA-triggered RNA interference. Caplen, N.J., Zheng, Z., Falgout, B., Morgan, R.A. Mol. Ther. (2002) [Pubmed]
  5. Chimeric dengue type 2 (vaccine strain PDK-53)/dengue type 1 virus as a potential candidate dengue type 1 virus vaccine. Huang, C.Y., Butrapet, S., Pierro, D.J., Chang, G.J., Hunt, A.R., Bhamarapravati, N., Gubler, D.J., Kinney, R.M. J. Virol. (2000) [Pubmed]
  6. Structural basis of NEDD8 ubiquitin discrimination by the deNEDDylating enzyme NEDP1. Shen, L.N., Liu, H., Dong, C., Xirodimas, D., Naismith, J.H., Hay, R.T. EMBO J. (2005) [Pubmed]
  7. Mdm2-mediated NEDD8 Modification of TAp73 Regulates Its Transactivation Function. Watson, I.R., Blanch, A., Lin, D.C., Ohh, M., Irwin, M.S. J. Biol. Chem. (2006) [Pubmed]
  8. Identification and characterization of DEN1, a deneddylase of the ULP family. Gan-Erdene, T., Nagamalleswari, K., Yin, L., Wu, K., Pan, Z.Q., Wilkinson, K.D. J. Biol. Chem. (2003) [Pubmed]
  9. Derivation and characterization of a dengue type 1 host range-restricted mutant virus that is attenuated and highly immunogenic in monkeys. Markoff, L., Pang, X., Houng Hs, H.S., Falgout, B., Olsen, R., Jones, E., Polo, S. J. Virol. (2002) [Pubmed]
  10. Molecular epidemiology of dengue-1 and dengue-4 viruses. Chungue, E., Cassar, O., Drouet, M.T., Guzman, M.G., Laille, M., Rosen, L., Deubel, V. J. Gen. Virol. (1995) [Pubmed]
  11. Dengue virus-specific human CD4+ T-lymphocyte responses in a recipient of an experimental live-attenuated dengue virus type 1 vaccine: bulk culture proliferation, clonal analysis, and precursor frequency determination. Green, S., Kurane, I., Edelman, R., Tacket, C.O., Eckels, K.H., Vaughn, D.W., Hoke, C.H., Ennis, F.A. J. Virol. (1993) [Pubmed]
  12. Dengue 1 virus binding to human hepatoma HepG2 and simian Vero cell surfaces differs. Marianneau, P., Mégret, F., Olivier, R., Morens, D.M., Deubel, V. J. Gen. Virol. (1996) [Pubmed]
  13. Identification of B-cell epitope of dengue virus type 1 and its application in diagnosis of patients. Wu, H.C., Huang, Y.L., Chao, T.T., Jan, J.T., Huang, J.L., Chiang, H.Y., King, C.C., Shaio, M.F. J. Clin. Microbiol. (2001) [Pubmed]
  14. Evaluation of the severe combined immunodeficient (SCID) mouse as an animal model for dengue viral infection. Wu, S.J., Hayes, C.G., Dubois, D.R., Windheuser, M.G., Kang, Y.H., Watts, D.M., Sieckmann, D.G. Am. J. Trop. Med. Hyg. (1995) [Pubmed]
  15. Structure of a complex between Nedd8 and the Ulp/Senp protease family member Den1. Reverter, D., Wu, K., Erdene, T.G., Pan, Z.Q., Wilkinson, K.D., Lima, C.D. J. Mol. Biol. (2005) [Pubmed]
  16. Identification and characterization of carbohydrate molecules in Mammalian cells recognized by dengue virus type 2. Aoki, C., Hidari, K.I., Itonori, S., Yamada, A., Takahashi, N., Kasama, T., Hasebe, F., Islam, M.A., Hatano, K., Matsuoka, K., Taki, T., Guo, C.T., Takahashi, T., Sakano, Y., Suzuki, T., Miyamoto, D., Sugita, M., Terunuma, D., Morita, K., Suzuki, Y. J. Biochem. (2006) [Pubmed]
  17. CAND1 enhances deneddylation of CUL1 by COP9 signalosome. Min, K.W., Kwon, M.J., Park, H.S., Park, Y., Yoon, S.K., Yoon, J.B. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  18. A dengue outbreak among camp participants in a Caribbean island, 1995. Lyerla, R., Rigau-Pérez, J.G., Vorndam, A.V., Reiter, P., George, A.M., Potter, I.M., Gubler, D.J. Journal of travel medicine : official publication of the International Society of Travel Medicine and the Asia Pacific Travel Health Association. (2000) [Pubmed]
  19. A model of the real-time correlation of viral titers with immune reactions in antibody-dependent enhancement of dengue-2 infections. Chen, R.F., Yeh, W.T., Yang, M.Y., Yang, K.D. FEMS Immunol. Med. Microbiol. (2001) [Pubmed]
  20. Differences between cell membrane fusion activities of two dengue type-1 isolates reflect modifications of viral structure. Desprès, P., Frenkiel, M.P., Deubel, V. Virology (1993) [Pubmed]
  21. Flow cytometry compared with indirect immunofluorescence for rapid detection of dengue virus type 1 after amplification in tissue culture. Kao, C.L., Wu, M.C., Chiu, Y.H., Lin, J.L., Wu, Y.C., Yueh, Y.Y., Chen, L.K., Shaio, M.F., King, C.C. J. Clin. Microbiol. (2001) [Pubmed]
  22. Optimized diagnosis of acute dengue fever in Swedish travelers by a combination of reverse transcription-PCR and immunoglobulin M detection. Lindegren, G., Vene, S., Lundkvist, A., Falk, K.I. J. Clin. Microbiol. (2005) [Pubmed]
  23. Molecular epidemiological study of dengue virus type 1 in Taiwan. Hwang, K.P., Chu, P.Y., Tung, Y.C., Wang, H.L., Yueh, Y.Y., Wu, Y.C., Chin, C., Lin, K.H. J. Med. Virol. (2003) [Pubmed]
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