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Gene Review

USP8  -  ubiquitin specific peptidase 8

Homo sapiens

Synonyms: Deubiquitinating enzyme 8, HumORF8, KIAA0055, SPG59, UBPY, ...
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High impact information on USP8

  • UBPY function is essential for effective downregulation but is likely to be multifaceted, encompassing activity against both K63-linked and K48-linked polyubiquitin chains and including regulation of the stability of ESCRT-associated proteins such as STAM, by reversing their ubiquitination [1].
  • By increasing or decreasing the cellular abundance of UBPY or by overexpressing a catalytic site mutant, we detect substantial changes in the total pattern of protein ubiquitination, which correlate stringently with cell proliferation [2].
  • UBPY accumulates upon growth stimulation of starved human fibroblasts, and its levels decrease in response to growth arrest induced by cell-cell contact [2].
  • Inhibition of UBPY accumulation by antisense plasmid microinjection prevents fibroblasts from entering S-phase in response to serum stimulation [2].
  • The USP8 rhodanese and catalytic domains mediated Nrdp1 binding [3].

Biological context of USP8

  • Amino-terminal Dimerization, NRDP1-Rhodanese Interaction, and Inhibited Catalytic Domain Conformation of the Ubiquitin-specific Protease 8 (USP8) [4].
  • Phosphorylation of the deubiquitinating enzyme USP8 at serine 680 was found essential for its interaction with 14-3-3epsilon and for maintaining USP8 in the cytosol [5].
  • The specific function of the human homolog hUBPy is not defined, although its expression was correlated with cell proliferation [6].
  • Thus, UBPY may play a regulatory role in the degradation by interaction with the SH3 domain of Hbp via the novel SH3-binding motif [7].
  • The cellular functions of UBPY are complex but clearly distinct from those of the Lys-63-ubiquitin-specific protease, AMSH, with which it shares a binding site on the SH3 domain of STAM [8].

Anatomical context of USP8

  • Catalytically inactive UBPY localizes to endosomes, which accumulate ubiquitinated proteins [8].
  • These results suggest that UBPY regulates the level of protein ubiquitination on endosomes, which is required for maintaining the morphology of the organelle [9].

Associations of USP8 with chemical compounds

  • UBPY is a ubiquitin-specific protease that can deubiquitinate monoubiquitinated receptor tyrosine kinases, as well as process Lys-48- and Lys-63-linked polyubiquitin to lower denomination forms in vitro [8].

Regulatory relationships of USP8

  • We also show that in common with AMSH, UBPY deubiquitinating enzyme activity can be stimulated by STAM but is unresponsive to its cognate CHMPs [10].

Other interactions of USP8


Analytical, diagnostic and therapeutic context of USP8

  • We have identified and characterized a novel human ubiquitin isopeptidase, UBPY, which both as a recombinant protein and upon immunoprecipitation from cell extracts is able to cleave linear or isopeptide-linked ubiquitin chains [2].


  1. Endocytosis: the DUB version. Clague, M.J., Urb??, S. Trends Cell Biol. (2006) [Pubmed]
  2. UBPY: a growth-regulated human ubiquitin isopeptidase. Naviglio, S., Mattecucci, C., Matoskova, B., Nagase, T., Nomura, N., Di Fiore, P.P., Draetta, G.F. EMBO J. (1998) [Pubmed]
  3. Stabilization of the E3 ubiquitin ligase Nrdp1 by the deubiquitinating enzyme USP8. Wu, X., Yen, L., Irwin, L., Sweeney, C., Carraway, K.L. Mol. Cell. Biol. (2004) [Pubmed]
  4. Amino-terminal Dimerization, NRDP1-Rhodanese Interaction, and Inhibited Catalytic Domain Conformation of the Ubiquitin-specific Protease 8 (USP8). Avvakumov, G.V., Walker, J.R., Xue, S., Finerty, P.J., Mackenzie, F., Newman, E.M., Dhe-Paganon, S. J. Biol. Chem. (2006) [Pubmed]
  5. Identification of 14-3-3epsilon substrates from embryonic murine brain. Ballif, B.A., Cao, Z., Schwartz, D., Carraway, K.L., Gygi, S.P. J. Proteome Res. (2006) [Pubmed]
  6. Cloning and characterization of mouse UBPy, a deubiquitinating enzyme that interacts with the ras guanine nucleotide exchange factor CDC25(Mm)/Ras-GRF1. Gnesutta, N., Ceriani, M., Innocenti, M., Mauri, I., Zippel, R., Sturani, E., Borgonovo, B., Berruti, G., Martegani, E. J. Biol. Chem. (2001) [Pubmed]
  7. A deubiquitinating enzyme UBPY interacts with the Src homology 3 domain of Hrs-binding protein via a novel binding motif PX(V/I)(D/N)RXXKP. Kato, M., Miyazawa, K., Kitamura, N. J. Biol. Chem. (2000) [Pubmed]
  8. The Ubiquitin Isopeptidase UBPY Regulates Endosomal Ubiquitin Dynamics and Is Essential for Receptor Down-regulation. Row, P.E., Prior, I.A., McCullough, J., Clague, M.J., Urbé, S. J. Biol. Chem. (2006) [Pubmed]
  9. A deubiquitinating enzyme UBPY regulates the level of protein ubiquitination on endosomes. Mizuno, E., Kobayashi, K., Yamamoto, A., Kitamura, N., Komada, M. Traffic (2006) [Pubmed]
  10. The MIT domain of UBPY constitutes a CHMP binding and endosomal localization signal required for efficient epidermal growth factor receptor degradation. Row, P.E., Liu, H., Hayes, S., Welchman, R., Charalabous, P., Hofmann, K., Clague, M.J., Sanderson, C.M., Urbé, S. J. Biol. Chem. (2007) [Pubmed]
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