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ubiquitin-proteasome system

Sunday 13 July 2003

Definition: The proteasome is the complete repertoire of proteases that are produced by organisms. The ubiquitin-proteasome pathway is responsible for the degradation of many cytosolic and nuclear proteins. Proteins to be degraded by this process are first conjugated to ubiquitin and then degraded within a large cytoplasmic proteolytic organelle called the proteasome.

This pathway is thought to be responsible for the accelerated proteolysis seen in a variety of catabolic conditions, including cancer cachexia.

The proteasome controls many cellular processes by degrading a large number of regulatory proteins.

Most proteins are targeted to the proteasome through covalent tagging by a chain consisting of several copies of the small protein ubiquitin.

Hul5 and Ubp6

Hul5 and Ubp6 regulate degradation further, when bound to the proteasome.

Hul5 promotes degradation by extending the number of ubiquitin moieties in the tag on substrates, whereas Ubp6 antagonizes degradation by trimming ubiquitin from the tag.

The balance between these two opposing activities might control the substrate specificity of the proteasome and adjusting the balance would provide a new level of degradation control.

Pathology of proteasome - Pathology of proteasomal degradation

- neurodegenerative diseases (Parkinson disease, Huntington disease)

  • protein misfolding and protein aggregation
  • inclusion bodies and other aggregates within cells.
  • aggregates often contain ubiquitin, which is the signal for proteolysis by the 26S proteasome, and chaperone proteins that are involved in the refolding of misfolded proteins.
  • identification of disease-causing mutations in genes coding for several ubiquitin-proteasome pathway proteins in Parkinson disease.

- Frequent mutations of genes encoding ubiquitin-mediated proteolysis pathway components in clear cell renal cell carcinoma. (22138691)

  • frequent mutations in the ubiquitin-mediated proteolysis pathway (UMPP).
  • alterations in the UMPP were significantly associated with overexpression of HIF1α and HIF2α in the tumors.
  • potential contribution of UMPP to ccRCC tumorigenesis through the activation of the hypoxia regulatory network.

Pathogenesis

- The ubiquitin-proteasome pathway is thought to be responsible for the accelerated proteolysis seen in a variety of catabolic conditions, including cancer cachexia.

- Dysfunction of ubiquitin-proteasome degradation (UPD) in neurons

Protein clearance appears to be particularly important for the viability of post-mitotic neurons. UPD dysfunction is directly implicated in several neurodegenerative disorders, the most prominent of which is Parkinson disease, the second most common neurodegenerative disorder in humans.

Mutations in the gene that encodes parkin, an E3 ubiquitin-protein ligase that is expressed highly in the brain, causes autosomal recessive juvenile parkinsonism (ARJP).

As an E3 enzyme, parkin targets several proteins for degradation, and in neuroblastoma cell lines it accumulates and is concentrated in the centrosomal region on treatment with lactacystin. Additionally, co-immunoprecipitation assays have demonstrated that parkin physically binds to gamma -tubulin both in vivo in rat brains as well as in vitro in HEK293 cells.

Furthermore, except in ARJP, Parkinson disease is usually associated with Lewy bodies - intracytoplasmic inclusions containing alpha-synuclein and ubiquitin, as well as other components that await biochemical identification.

alpha-Synuclein is a substrate of the UPD system, and the Ala53Thr and Ala30Pro mutant peptides that are found in some patients, are degraded 50% slower than those of the wild type, possibly accounting for their accelerated aggregation into fibrils of the mutant protein.

Additionally, defects in UPD probably affect the clearance of alpha-synuclein in a more generalized way, as increased intracellular protein concentration promotes alpha-synuclein aggregation through a ’molecular crowding’ effect.

As such, even though alpha-synuclein is not itself a centrosomal protein, it seems that the ability of the centrosome-associated UPD system to clear misfolded proteins is central to the pathogenesis of all forms of Parkinson disease.

The emerging theme deduced from the functional properties of the Parkinson disease proteins is that defective protein degradation underlies the pathogenesis of this disease.

Therefore, given that the centrosome is linked to the UPD system both structurally and functionally, it is reasonable to propose that centrosomal dysfunction has a role in the pathogenesis of protein clearance disorders, and that the evaluation of centrosomal integrity and function in progressive phenotypes might yield new functional insights into poorly understood pathologies.

The link between centrosomal dysfunction and protein clearance disorders could be direct, for example by affecting the recruitment and/or anchoring of centrosomally located proteins such as parkin, or indirect, through the destabilization or disorganization of the pericentriolar region, where the bulk of proteasome-dependent protein degradation occurs.

As such, it might be useful to investigate not only a causative link between centrosomal dysfunction and UPD-based disorders, but also to speculate that centrosomal perturbation might be important in modulating the rate of progression and/or severity of such phenotypes.

See also

- ubiquitin-proteasome system (UPS)
- antigen processing by the proteasome
- degradation of misfolded proteins
- proteasome inhibition

Reviews

- Kraut DA, Prakash S, Matouschek A. To degrade or release: ubiquitin-chain remodeling. Trends Cell Biol. 2007 Sep;17(9):419-21. PMID: 17900906

- Ulrich HD. Mutual interactions between the SUMO and ubiquitin systems: a plea of no contest. Trends Cell Biol. 2005 Oct;15(10):525-32. PMID: 16125934

- Hol EM, van Leeuwen FW, Fischer DF. The proteasome in Alzheimer’s disease and Parkinson’s disease: lessons from ubiquitin B+1. Trends Mol Med. 2005 Nov;11(11):488-95. PMID: 1621379021

- Ross CA, Pickart CM. The ubiquitin-proteasome pathway in Parkinson’s disease and other neurodegenerative diseases. Trends Cell Biol. 2004 Dec;14(12):703-11. PMID: 15564047

- Song S, Jung YK. Alzheimer’s disease meets the ubiquitin-proteasome system. Trends Mol Med. 2004 Nov;10(11):565-70. PMID: 15519283

- Jiang YH, Beaudet AL. Human disorders of ubiquitination and proteasomal degradation. Curr Opin Pediatr. 2004 Aug;16(4):419-26. PMID: 15273504

- Adams J. The proteasome: a suitable antineoplastic target. Nat Rev Cancer. 2004 May;4(5):349-60. PMID: 15122206

- Ciechanover A, Ben-Saadon R. N-terminal ubiquitination: more protein substrates join in. Trends Cell Biol. 2004 Mar;14(3):103-6. PMID: 15055197

- Forster A, Hill CP. Proteasome degradation: enter the substrate. Trends Cell Biol. 2003 Nov;13(11):550-3. PMID: 14573346

- Dimcheff DE, Portis JL, Caughey B. Prion proteins meet protein quality control. Trends Cell Biol. 2003 Jul;13(7):337-40. PMID: 12837603

- Adams J. Proteasome inhibition: a novel approach to cancer therapy. Trends Mol Med. 2002;8(4 Suppl):S49-54. PMID: 11927288

- McNaught KS, Olanow CW, Halliwell B, Isacson O, Jenner P. Failure of the ubiquitin-proteasome system in Parkinson’s disease. Nat Rev Neurosci. 2001 Aug;2(8):589-94. PMID: 11484002

- Kloetzel PM. Antigen processing by the proteasome. Nat Rev Mol Cell Biol. 2001 Mar;2(3):179-87. PMID: 11265247

- Hirsch C, Ploegh HL. Intracellular targeting of the proteasome. Trends Cell Biol. 2000 Jul;10(7):268-72. PMID: 10856929

- Carrard G, et al: Impairment of proteasome structure and function in aging. Int J Biochem Cell Biol 34:1461, 2002.

- Glickman MH, Ciechanover A: The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. Physiol Rev 82:373, 2002.

References

- Frequent mutations of genes encoding ubiquitin-mediated proteolysis pathway components in clear cell renal cell carcinoma. Guo G, Gui Y, Gao S, Tang A et al. Nat Genet. 2011 Dec 4;44(1):17-9. PMID: 22138691