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Gene Review

VPS4A  -  vacuolar protein sorting 4 homolog A (S....

Homo sapiens

Synonyms: FLJ22197, Protein SKD2, SKD1, SKD1A, SKD2, ...
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Disease relevance of VPS4A


High impact information on VPS4A

  • HIV-1 budding appears to require Vps4 and Tsg101-two proteins that have links to endosomal sorting machinery [4].
  • The subsequent dissociation of ESCRT complexes from endosomes requires Vps4, a member of the AAA family of adenosine triphosphatases [5].
  • Here, we report the solution structure of the N-terminal VPS4A microtubule interacting and transport (MIT) domain and demonstrate that the VPS4A MIT domain binds the C-terminal half of the ESCRT-III protein, CHMP1B (Kd = 20 +/- 13 microM) [6].
  • Finally, a dominant negative mutant of the VPS4 protein was shown to block the enhanced alpha1 microglobulin secretion in ORF3-expressing hepatocytes [7].
  • Together with earlier studies, our work suggests that a variety of ESCRT-III-containing polymers can assemble on membranes and recruit SKD1 during formation of the MVB [8].

Biological context of VPS4A

  • A BLAST search of the human genome database with the human VPS4A sequence yielded a double match, most likely due to a faulty assembly of sequence contigs in the human draft sequence [9].
  • The vacuolar protein sorting defect of vps4 mutant yeast cells was complemented completely by heterologous expressed human VPS4-B protein, and partially by the human VPS4-A protein [10].
  • We isolated the mouse SKD1 locus and found that the SKD1 gene is split into 11 exons covering a region of 29kb of the genome [11].
  • Analysis of the promoter region, which revealed features common for 'housekeeping genes', is consistent with previous results of a mouse multi-tissue Northern blot, confirming that SKD1 is a ubiquitously expressed gene [11].
  • The phenotype described here is largely consistent with the defects in vacuolar sorting associated with class E vps mutants in yeast, and a role for mammalian VPS4 is discussed in this context [12].

Anatomical context of VPS4A

  • Sorting of receptors from the early endosome to the recycling compartment or to the trans-Golgi network was not significantly affected, and no mutant hVPS4 associated with these compartments [12].
  • To investigate the function of mammalian VPS4 in endosomal trafficking, we have transiently expressed wild-type or ATPase-defective human VPS4 (hVPS4) in cultured cells [12].
  • Here, we show that an ATPase-deficient mutant of hVPS4 (hVPS4(EQ)) increases the association of bilayered coats with endosomal vacuoles [13].
  • An ATPase-defective Vps4-A mutant, Vps4-A(E228Q), expressed in HeLa cells was accumulated in the early endosomes [14].
  • All tested VPS4 fusion proteins were found in the cytosol [9].

Associations of VPS4A with chemical compounds

  • Vps4-A associated with both guanosine 5'-[beta-thio]triphosphate-bound active and guanosine 5'-[beta-thio]diphosphate-bound inactive forms of Rnd2 [14].
  • SKD1(E235Q) associated with NPC1 on the endosomal membrane, whereas wild-type SKD1 associated with NPC1 only when cells were depleted of cholesterol [15].

Physical interactions of VPS4A

  • These results suggest that Rnd2 is involved in the regulation of endosomal trafficking via direct binding to Vps4-A [14].

Other interactions of VPS4A

  • 3) Like TGS101, VPS37B became trapped on aberrant endosomal compartments in the presence of VPS4A proteins lacking ATPase activity [16].
  • Fluorescent in situ hybridization and radiation hybrid analyses demonstrated that human and mouse VPS4A/a and VPS4B/b are located on syntenic chromosomal regions [9].
  • L-domains can functionally interact with cellular proteins involved in vacuolar sorting (VPS4A and TSG101) and endocytic pathways (Nedd4), suggesting involvement of these pathways in virus budding [1].
  • Consistent with a role of VPS4A in the budding of both PPPY and PTAP motif-containing viruses, the overexpression of ATPase-defective GFP-VPS4A fusion proteins blocked both wild-type and PSAP mutant virus release [17].


  1. Budding of PPxY-containing rhabdoviruses is not dependent on host proteins TGS101 and VPS4A. Irie, T., Licata, J.M., McGettigan, J.P., Schnell, M.J., Harty, R.N. J. Virol. (2004) [Pubmed]
  2. Tsg101 and the vacuolar protein sorting pathway are essential for HIV-1 budding. Garrus, J.E., von Schwedler, U.K., Pornillos, O.W., Morham, S.G., Zavitz, K.H., Wang, H.E., Wettstein, D.A., Stray, K.M., Côté, M., Rich, R.L., Myszka, D.G., Sundquist, W.I. Cell (2001) [Pubmed]
  3. Potent inhibition of human Hepatitis B virus replication by a host factor Vps4. Kian Chua, P., Lin, M.H., Shih, C. Virology (2006) [Pubmed]
  4. Resistance is futile: assimilation of cellular machinery by HIV-1. Perez, O.D., Nolan, G.P. Immunity (2001) [Pubmed]
  5. Did2 coordinates Vps4-mediated dissociation of ESCRT-III from endosomes. Nickerson, D.P., West, M., Odorizzi, G. J. Cell Biol. (2006) [Pubmed]
  6. Structure and ESCRT-III protein interactions of the MIT domain of human VPS4A. Scott, A., Gaspar, J., Stuchell-Brereton, M.D., Alam, S.L., Skalicky, J.J., Sundquist, W.I. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  7. Enhanced alpha1 microglobulin secretion from Hepatitis E virus ORF3-expressing human hepatoma cells is mediated by the tumor susceptibility gene 101. Surjit, M., Oberoi, R., Kumar, R., Lal, S.K. J. Biol. Chem. (2006) [Pubmed]
  8. Interaction of the mammalian endosomal sorting complex required for transport (ESCRT) III protein hSnf7-1 with itself, membranes, and the AAA+ ATPase SKD1. Lin, Y., Kimpler, L.A., Naismith, T.V., Lauer, J.M., Hanson, P.I. J. Biol. Chem. (2005) [Pubmed]
  9. Comparative sequence and expression analyses of four mammalian VPS4 genes. Beyer, A., Scheuring, S., Müller, S., Mincheva, A., Lichter, P., Köhrer, K. Gene (2003) [Pubmed]
  10. Mammalian cells express two VPS4 proteins both of which are involved in intracellular protein trafficking. Scheuring, S., Röhricht, R.A., Schöning-Burkhardt, B., Beyer, A., Müller, S., Abts, H.F., Köhrer, K. J. Mol. Biol. (2001) [Pubmed]
  11. Cloning, characterisation, and functional expression of the Mus musculus SKD1 gene in yeast demonstrates that the mouse SKD1 and the yeast VPS4 genes are orthologues and involved in intracellular protein trafficking. Scheuring, S., Bodor, O., Röhricht, R.A., Müller, S., Beyer, A., Köhrer, K. Gene (1999) [Pubmed]
  12. ATPase-defective mammalian VPS4 localizes to aberrant endosomes and impairs cholesterol trafficking. Bishop, N., Woodman, P. Mol. Biol. Cell (2000) [Pubmed]
  13. ATPase-deficient hVPS4 impairs formation of internal endosomal vesicles and stabilizes bilayered clathrin coats on endosomal vacuoles. Sachse, M., Strous, G.J., Klumperman, J. J. Cell. Sci. (2004) [Pubmed]
  14. Vps4-A (vacuolar protein sorting 4-A) is a binding partner for a novel Rho family GTPase, Rnd2. Tanaka, H., Fujita, H., Katoh, H., Mori, K., Negishi, M. Biochem. J. (2002) [Pubmed]
  15. Cholesterol depletion facilitates ubiquitylation of NPC1 and its association with SKD1/Vps4. Ohsaki, Y., Sugimoto, Y., Suzuki, M., Hosokawa, H., Yoshimori, T., Davies, J.P., Ioannou, Y.A., Vanier, M.T., Ohno, K., Ninomiya, H. J. Cell. Sci. (2006) [Pubmed]
  16. The human endosomal sorting complex required for transport (ESCRT-I) and its role in HIV-1 budding. Stuchell, M.D., Garrus, J.E., Müller, B., Stray, K.M., Ghaffarian, S., McKinnon, R., Kräusslich, H.G., Morham, S.G., Sundquist, W.I. J. Biol. Chem. (2004) [Pubmed]
  17. The Mason-Pfizer monkey virus PPPY and PSAP motifs both contribute to virus release. Gottwein, E., Bodem, J., Müller, B., Schmechel, A., Zentgraf, H., Kräusslich, H.G. J. Virol. (2003) [Pubmed]
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