Skip to main content

Hrs inhibits citron kinase-mediated HIV-1 budding via its FYVE domain

Abstract

Hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) is a key component of the endosomal sorting complexes required for transport and has been demonstrated to play a regulatory role in endocytosis/exocytosis and the accumulation of internal vesicles in multivesicular bodies. Citron kinase is a Ser/The kinase that we previously reported to enhance human immunodeficiency virus type 1 (HIV-1) virion production. However, the relationship between Hrs and citron kinase in HIV-1 production remains elusive. Here, we report that Hrs interacts with citron kinase via its FYVE domain. Overexpression of Hrs or the FYVE domain resulted in a significant decrease in HIV-1 virion production. Depletion of Hrs by RNA interference in HEK293T cells increased HIV-1 virion production and enhanced the activity of citron kinase. These data suggest that Hrs inhibits HIV-1 production by inhibiting citron kinase-mediated exocytosis.

References

  • Bache, K.G., Brech, A., Mehlum, A., and Stenmark, H. (2003). Hrs regulates multivesicular body formation via ESCRT recruitment to endosomes. J Cell Biol 162, 435–442.

    Article  Google Scholar 

  • Bean, A.J., Seifert, R., Chen, Y.A., Sacks, R., and Scheller, R.H. (1997). Hrs-2 is an ATPase implicated in calcium-regulated secretion. Nature 385, 826–829.

    Article  Google Scholar 

  • Bouamr, F., Houck-Loomis, B.R., De Los Santos, M., Casaday, R.J., Johnson, M.C., and Goff, S.P. (2007). The C-terminal portion of the Hrs protein interacts with Tsg101 and interferes with human immunodeficiency virus type 1 Gag particle production. J Virol 81, 2909–2922.

    Article  Google Scholar 

  • Bouamr, F., Melillo, J.A., Wang, M.Q., Nagashima, K., de Los Santos, M., Rein, A., and Goff, S.P. (2003). PPPYVEPTAP motif is the late domain of human T-cell leukemia virus type 1 Gag and mediates its functional interaction with cellular proteins Nedd4 and Tsg101 [corrected]. J Virol 77, 11882–11895.

    Article  Google Scholar 

  • Dong, X., Li, H., Derdowski, A., Ding, L., Burnett, A., Chen, X., Peters, T.R., Dermody, T.S., Woodruff, E., Wang, J.J., et al. (2005). AP-3 directs the intracellular trafficking of HIV-1 Gag and plays a key role in particle assembly. Cell 120, 663–674.

    Article  Google Scholar 

  • Finzi, A., Orthwein, A., Mercier, J., and Cohen, E.A. (2007). Productive human immunodeficiency virus type 1 assembly takes place at the plasma membrane. J Virol 81, 7476–7490.

    Article  Google Scholar 

  • Kwong, J., Roundabush, F.L., Hutton Moore, P., Montague, M., Oldham, W., Li, Y., Chin, L.S., and Li, L. (2000). Hrs interacts with SNAP-25 and regulates Ca(2 +)-dependent exocytosis. J Cell Sci 113, 2273–2284.

    Google Scholar 

  • Loomis, R.J., Holmes, D.A., Elms, A., Solski, P.A., Der, C.J., and Su, L. (2006). Citron kinase, a RhoA effector, enhances HIV-1 virion production by modulating exocytosis. Traffic 7, 1643–1653.

    Article  Google Scholar 

  • Mai, Y., and Gao, G. (2010). Expression of IMP1 enhances production of murine leukemia virus vector by facilitating viral genomic RNA packaging. PLoS One 5, e15881.

    Article  Google Scholar 

  • McCullough, J., Fisher, R.D., Whitby, F.G., Sundquist, W.I., and Hill, C.P. (2008). ALIX-CHMP4 interactions in the human ESCRT pathway. Proc Natl Acad Sci U S A 105, 7687–7691.

    Article  Google Scholar 

  • Mills, I.G., Jones, A.T., and Clague, M.J. (1998). Involvement of the endosomal autoantigen EEA1 in homotypic fusion of early endosomes. Curr Biol 8, 881–884.

    Article  Google Scholar 

  • Ono, A., and Freed, E.O. (2004). Cell-type-dependent targeting of human immunodeficiency virus type 1 assembly to the plasma membrane and the multivesicular body. J Virol 78, 1552–1563.

    Article  Google Scholar 

  • Paillart, J.C., and Göttlinger, H.G. (1999). Opposing effects of human immunodeficiency virus type 1 matrix mutations support a myristyl switch model of gag membrane targeting. J Virol 73, 2604–2612.

    Google Scholar 

  • Perez-Caballero, D., Zang, T., Ebrahimi, A., McNatt, M.W., Gregory, D.A., Johnson, M.C., and Bieniasz, P.D. (2009). Tetherin inhibits HIV-1 release by directly tethering virions to cells. Cell 139, 499–511.

    Article  Google Scholar 

  • Pornillos, O., Alam, S.L., Davis, D.R., and Sundquist, W.I. (2002). Structure of the Tsg101 UEV domain in complex with the PTAP motif of the HIV-1 p6 protein. Nat Struct Biol 9, 812–817.

    Google Scholar 

  • Pridgeon, J.W., Webber, E.A., Sha, D., Li, L., and Chin, L.S. (2009). Proteomic analysis reveals Hrs ubiquitin-interacting motifmediated ubiquitin signaling in multiple cellular processes. FEBS J 276, 118–131.

    Article  Google Scholar 

  • Simonsen, A., Lippé, R., Christoforidis, S., Gaullier, J.M., Brech, A., Callaghan, J., Toh, B.H., Murphy, C., Zerial, M., and Stenmark, H. (1998). EEA1 links PI(3)K function to Rab5 regulation of endosome fusion. Nature 394, 494–498.

    Article  Google Scholar 

  • Spearman, P., Horton, R., Ratner, L., and Kuli-Zade, I. (1997). Membrane binding of human immunodeficiency virus type 1 matrix protein in vivo supports a conformational myristyl switch mechanism. J Virol 71, 6582–6592.

    Google Scholar 

  • Strack, B., Calistri, A., Craig, S., Popova, E., and Göttlinger, H.G. (2003). AIP1/ALIX is a binding partner for HIV-1 p6 and EIAV p9 functioning in virus budding. Cell 114, 689–699.

    Article  Google Scholar 

  • Stuchell-Brereton, M.D., Skalicky, J.J., Kieffer, C., Karren, M.A., Ghaffarian, S., and Sundquist, W.I. (2007). ESCRT-III recognition by VPS4 ATPases. Nature 449, 740–744.

    Article  Google Scholar 

  • Tang, C., Loeliger, E., Luncsford, P., Kinde, I., Beckett, D., and Summers, M.F. (2004). Entropic switch regulates myristate exposure in the HIV-1 matrix protein. Proc Natl Acad Sci U S A 101, 517–522.

    Article  Google Scholar 

  • VerPlank, L., Bouamr, F., LaGrassa, T.J., Agresta, B., Kikonyogo, A., Leis, J., and Carter, C.A. (2001). Tsg101, a homologue of ubiquitinconjugating (E2) enzymes, binds the L domain in HIV type 1 Pr55 (Gag). Proc Natl Acad Sci U S A 98, 7724–7729.

    Article  Google Scholar 

  • Zhai, Q., Fisher, R.D., Chung, H.Y., Myszka, D.G., Sundquist, W.I., and Hill, C.P. (2008). Structural and functional studies of ALIX interactions with YPX(n)L late domains of HIV-1 and EIAV. Nat Struct Mol Biol 15, 43–49.

    Article  Google Scholar 

  • Zhou, W., and Resh, M.D. (1996). Differential membrane binding of the human immunodeficiency virus type 1 matrix protein. J Virol 70, 8540–8548.

    Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Guangxia Gao.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Ding, J., Su, L. & Gao, G. Hrs inhibits citron kinase-mediated HIV-1 budding via its FYVE domain. Protein Cell 2, 470–476 (2011). https://doi.org/10.1007/s13238-011-1053-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13238-011-1053-y

Keywords

  • citron kinase
  • Hrs
  • HIV-1 budding