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Gene Review

UBQLN1  -  ubiquilin 1

Homo sapiens

Synonyms: DA41, DSK2, PLIC-1, PLIC1, Protein linking IAP with cytoskeleton 1, ...
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Disease relevance of UBQLN1


Psychiatry related information on UBQLN1


High impact information on UBQLN1

  • The Dsk2 mutation is likely to impair intermediate filament assembly, leading to cytolysis of suprabasal keratinocytes and secondary hyperkeratosis and melanocytosis [7].
  • Thus, PLIC-1 inhibits Gi signaling by direct association with Gbetagamma; because it also interacts with CD47, a modulator of integrin function, it likely has a role integrating adhesion and signaling components of cell migration [8].
  • PLIC-1 prevented the SDF-1alpha-induced activation of phospholipase C, decreased ligand-induced internalization of SDF-1alpha receptor CXCR4 and inhibited chemotaxis signaled by a transfected Gi-coupled receptor [8].
  • PLIC-1, a newly described ubiquitin-related protein, inhibited both Jurkat migration toward SDF-1alpha and A431 wound healing, but the closely related PLIC-2 did not [8].
  • The ubiquitin-related protein PLIC-1 regulates heterotrimeric G protein function through association with Gbetagamma [8].

Chemical compound and disease context of UBQLN1


Biological context of UBQLN1

  • Our haplotype data suggest the presence of additional putative functional variants either in the UBQLN1 gene or nearby genes and provide strong justification for additional work in this region on chromosome 9 [6].
  • The purpose of this study was to confirm the reported association in a large case-control sample and to also examine the association of UBQLN1 SNPs with quantitative measures of AD progression, namely age-at-onset (AAO), disease duration and Mini-Mental State Examination (MMSE) score [6].
  • Recently, genetic variation in UBQLN1 has been shown to affect the risk of AD in two independent family-based samples [6].
  • In contrast, knockdown of ubiquilin-1 and -2 protein expression by RNAi (RNA interference) increased Pen-2 and nicastrin levels [10].
  • These studies implicate ubiquilin as an important factor in regulating PS biogenesis and metabolism [10].

Anatomical context of UBQLN1


Associations of UBQLN1 with chemical compounds


Physical interactions of UBQLN1

  • Here, we show that PLIC-1 also binds to the UIM proteins ataxin 3-a deubiquitinating enzyme-HSJ1a-a co-chaperone-and EPS15 (epidermal growth factor substrate 15)-an endocytic protein [13].
  • Using glutathione-S-transferase pull-down experiments, we show that the first ubiquitin-interacting motif of Eps15 (UIM1) interacts directly with the UBL domain of ubiquilin, whereas it does not bind to ubiquitinated proteins [14].

Regulatory relationships of UBQLN1

  • However, we show that ubiquilin promotes presenilin protein accumulation [1].
  • Furthermore, we show that the PS1-ubiquilin 1 interaction can be detected between endogenous proteins in primary neurons in vitro as well as in brain tissue of healthy controls and Alzheimer disease patients, providing evidence of its physiological relevance [15].
  • Collectively, our findings suggest that UBQLN1 may normally serve as a cytoplasmic "gatekeeper" that may control APP trafficking from intracellular compartments to the cell surface [11].

Other interactions of UBQLN1

  • Pulse-labeling experiments indicate that ubiquilin facilitates increased presenilin synthesis without substantially changing presenilin protein half-life [1].
  • Interestingly, overexpression of ubiquilin resulted in a decrease in Pen-2 and nicastrin levels, two essential components of the gamma-secretase complex [10].
  • We demonstrate that down-regulation of UBQLN1 accelerates the maturation and intracellular trafficking of APP, while not interfering with alpha-, beta-, or gamma-secretase levels or activity [11].
  • We show that knockdown of PLIC-1 and EPS15 by RNA interference reduces aggresome formation [13].
  • Recently, we have identified a new protein (DA41) which can associate with candidate tumor-suppressor DAN protein [16].

Analytical, diagnostic and therapeutic context of UBQLN1

  • Immunohistochemistry of human brain tissue with ubiquilin-specific antibodies revealed prominent staining of neurons [1].
  • Sequence analysis revealed that DA41 cDNA is 2,167 nucleotides in length and contains a single open reading frame (ORF) of 582 amino acids (61,945 daltons) [17].
  • In a synchronous 3Y1 cell culture, DA41 mRNA was expressed at a low level in quiescent cells; however, its level was significantly increased between the G1 and S phases of the cell cycle [17].
  • RESULTS: All seven patients showed decreased diffusion anisotropy and increased diffusion constant in the PLIC, with complete separation from a normal control group, including patients early in the course of the illness [18].


  1. Identification of ubiquilin, a novel presenilin interactor that increases presenilin protein accumulation. Mah, A.L., Perry, G., Smith, M.A., Monteiro, M.J. J. Cell Biol. (2000) [Pubmed]
  2. Role of ubiquilin associated with protein-disulfide isomerase in the endoplasmic reticulum in stress-induced apoptotic cell death. Ko, H.S., Uehara, T., Nomura, Y. J. Biol. Chem. (2002) [Pubmed]
  3. Ubiquilin-1 is a novel HASH-1-complexing protein that regulates levels of neuronal bHLH transcription factors in human neuroblastoma cells. Persson, P., Stockhausen, M.T., Påhlman, S., Axelson, H. Int. J. Oncol. (2004) [Pubmed]
  4. Suppression of polyglutamine-induced toxicity in cell and animal models of Huntington's disease by ubiquilin. Wang, H., Lim, P.J., Yin, C., Rieckher, M., Vogel, B.E., Monteiro, M.J. Hum. Mol. Genet. (2006) [Pubmed]
  5. Diffusion-tensor MR tractography of somatotopic organization of corticospinal tracts in the internal capsule: initial anatomic results in contradistinction to prior reports. Holodny, A.I., Gor, D.M., Watts, R., Gutin, P.H., Ulug, A.M. Radiology. (2005) [Pubmed]
  6. Genetic association of ubiquilin with Alzheimer's disease and related quantitative measures. Kamboh, M.I., Minster, R.L., Feingold, E., DeKosky, S.T. Mol. Psychiatry (2006) [Pubmed]
  7. Genetics of dark skin in mice. Fitch, K.R., McGowan, K.A., van Raamsdonk, C.D., Fuchs, H., Lee, D., Puech, A., Hérault, Y., Threadgill, D.W., Hrabé de Angelis, M., Barsh, G.S. Genes Dev. (2003) [Pubmed]
  8. The ubiquitin-related protein PLIC-1 regulates heterotrimeric G protein function through association with Gbetagamma. N'Diaye, E.N., Brown, E.J. J. Cell Biol. (2003) [Pubmed]
  9. GM1 up-regulates Ubiquilin 1 expression in human neuroblastoma cells and rat cortical neurons. Liu, Z., Ruan, Y., Yue, W., Zhu, Z., Hartmann, T., Beyreuther, K., Zhang, D. Neurosci. Lett. (2006) [Pubmed]
  10. Ubiquilin regulates presenilin endoproteolysis and modulates gamma-secretase components, Pen-2 and nicastrin. Massey, L.K., Mah, A.L., Monteiro, M.J. Biochem. J. (2005) [Pubmed]
  11. Ubiquilin 1 modulates amyloid precursor protein trafficking and abeta secretion. Hiltunen, M., Lu, A., Thomas, A.V., Romano, D.M., Kim, M., Jones, P.B., Xie, Z., Kounnas, M.Z., Wagner, S.L., Berezovska, O., Hyman, B.T., Tesco, G., Bertram, L., Tanzi, R.E. J. Biol. Chem. (2006) [Pubmed]
  12. Ubiquilin-1 regulates nicotine-induced up-regulation of neuronal nicotinic acetylcholine receptors. Ficklin, M.B., Zhao, S., Feng, G. J. Biol. Chem. (2005) [Pubmed]
  13. The UBL domain of PLIC-1 regulates aggresome formation. Heir, R., Ablasou, C., Dumontier, E., Elliott, M., Fagotto-Kaufmann, C., Bedford, F.K. EMBO Rep. (2006) [Pubmed]
  14. Ubiquilin recruits Eps15 into ubiquitin-rich cytoplasmic aggregates via a UIM-UBL interaction. Regan-Klapisz, E., Sorokina, I., Voortman, J., de Keizer, P., Roovers, R.C., Verheesen, P., Urbé, S., Fallon, L., Fon, E.A., Verkleij, A., Benmerah, A., van Bergen en Henegouwen, P.M. J. Cell. Sci. (2005) [Pubmed]
  15. Interaction between presenilin 1 and ubiquilin 1 as detected by fluorescence lifetime imaging microscopy and a high-throughput fluorescent plate reader. Thomas, A.V., Herl, L., Spoelgen, R., Hiltunen, M., Jones, P.B., Tanzi, R.E., Hyman, B.T., Berezovska, O. J. Biol. Chem. (2006) [Pubmed]
  16. Interaction of DA41, a DAN-binding protein, with the epidermal growth factor-like protein, S(1-5). Ozaki, T., Kondo, K., Nakamura, Y., Ichimiya, S., Nakagawara, A., Sakiyama, S. Biochem. Biophys. Res. Commun. (1997) [Pubmed]
  17. Identification of a new cellular protein that can interact specifically with DAN. Ozaki, T., Hishiki, T., Toyama, Y., Yuasa, S., Nakagawara, A., Sakiyama, S. DNA Cell Biol. (1997) [Pubmed]
  18. Diffusion tensor imaging in the diagnosis of primary lateral sclerosis. Uluğ, A.M., Grünewald, T., Lin, M.T., Kamal, A.K., Filippi, C.G., Zimmerman, R.D., Beal, M.F. Journal of magnetic resonance imaging : JMRI. (2004) [Pubmed]
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