The full content of Annals is available to subscribers

Subscribe/Learn More  >
Reviews |

Narrative Review: Protein Degradation and Human Diseases: The Ubiquitin Connection

Eyal Reinstein, MD, PhD; and Aaron Ciechanover, MD, DSc
[+] Article, Author, and Disclosure Information

From Meir General Hospital, Kfar-Saba, Israel, and Technion-Israel Institute of Technology, Haifa, Israel.

Acknowledgments: Dr. Reinstein thanks Monty Krieger, PhD, at Massachusetts Institute of Technology in Cambridge, Massachusetts, for his support and Tami Katzir, PhD, at Harvard University in Cambridge, Massachusetts, for her critical comments.

Grant Support: Research in Dr. Ciechanover's laboratory has been supported by a professorship from the Israel Cancer Research Fund USA and grants from the European Union; the Prostate Cancer Foundation, Israel; the Israel Science Foundation; and the Foundation for Promotion of Research in the Technion. Infrastructural equipment for Dr. Ciechanover's laboratory and for the Cancer and Vascular Biology Research Center was purchased with support from the Wolfson Charitable Fund.

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Eyal Reinstein, MD, PhD, Department of Internal Medicine B, Meir General Hospital and the Sackler School of Medicine, Tel-Aviv University, Kfar-Saba 95847, Israel; e-mail, eyalr@mit.edu.

Current Author Addresses: Dr. Reinstein: Department of Internal Medicine B, Meir General Hospital and the Sackler School of Medicine, Tel-Aviv University, Kfar-Saba 95847, Israel.

Dr. Ciechanover: Vascular and Cancer Biology Research Center, The Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa 31096, Israel.

Ann Intern Med. 2006;145(9):676-684. doi:10.7326/0003-4819-145-9-200611070-00010
Text Size: A A A

Between the 1950s and 1980s, many scientists focused on the process by which the genetic code is translated into proteome. However, little attention was devoted to the mechanism responsible for protein degradation. When researchers discovered the organelle lysosome, they assumed that cellular proteins were degraded within it. However, several independent lines of evidence strongly suggested that intracellular proteolysis was largely nonlysosomal. The discovery of the ubiquitin proteasome system (UPS) resolved this enigma. It is now recognized that degradation of intracellular proteins by the UPS is involved in the regulation of a broad array of cellular processes, including cell-cycle division; DNA repair, growth, and differentiation; quality control; and regulation of membrane receptors and ion channels. Not surprisingly, aberrations in thesystem have been implicated in the pathogenesis of numerous human diseases, and it seems that pharmacologic manipulation of the UPS might alter the outcome of many diseases, especially malignant conditions and possibly neurodegenerative and chronic inflammatory diseases. These findings have led to increasing efforts to develop mechanism-based drugs that modulate UPS activity, one of which is already on the market. In the near future, one can expect to see the development of new, potent, and highly specific drugs that target the degradation pathways of a single or a few proteins without affecting other proteins.


Grahic Jump Location
Figure 1.
Conjugation of ubiquitin to the protein substrate.

Ubiquitin is activated by the ubiquitin-activating enzyme, E1 [1], in a process that requires energy (adenosine triphosphate [ATP]). Ubiquitin is then transferred to a ubiquitin-conjugating enzyme, E2 [2]. E2 transfers the activated ubiquitin moiety to the protein substrate that is bound specifically to a unique ubiquitin ligase, E3 [3]. Successive conjugation of ubiquitin moieties to one another generates a polyubiquitin chain [4].

Grahic Jump Location
Grahic Jump Location
Figure 2.
Degradation of the ubiquitin-tagged substrate by the 26S proteasome.

The polyubiquitin chain serves as a binding and degradation signal for the 26S proteasome [1]. The substrate is degraded to short peptides [2], followed by a release of free and reusable ubiquitin molecules [3]. Proteasomal degradation also requires energy. ATP = adenosine triphosphate.

Grahic Jump Location
Grahic Jump Location
Figure 3.
Aberrations in the ubiquitin proteasome system and pathogenesis of human diseases.

Normal degradation of cellular proteins maintains them in a steady-state level [1]. When degradation is accelerated because of an increase in the level of an E3 (Skp2 in the case of p27, for example) or an ancillary protein that binds the substrate and targets it for degradation (for example, the human papillomavirus E6 oncoprotein that associates with p53 and targets it for degradation), the steady-state level of the protein decreases [2]. A mutation in an E3 enzyme or in the substrate's recognition motif (such as occurs in the Liddle syndrome) will result in decreased degradation and accumulation of the target substrate [3].

Grahic Jump Location




Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).


Submit a Comment/Letter
Submit a Comment/Letter

Summary for Patients

Clinical Slide Sets

Terms of Use

The In the Clinic® slide sets are owned and copyrighted by the American College of Physicians (ACP). All text, graphics, trademarks, and other intellectual property incorporated into the slide sets remain the sole and exclusive property of the ACP. The slide sets may be used only by the person who downloads or purchases them and only for the purpose of presenting them during not-for-profit educational activities. Users may incorporate the entire slide set or selected individual slides into their own teaching presentations but may not alter the content of the slides in any way or remove the ACP copyright notice. Users may make print copies for use as hand-outs for the audience the user is personally addressing but may not otherwise reproduce or distribute the slides by any means or media, including but not limited to sending them as e-mail attachments, posting them on Internet or Intranet sites, publishing them in meeting proceedings, or making them available for sale or distribution in any unauthorized form, without the express written permission of the ACP. Unauthorized use of the In the Clinic slide sets will constitute copyright infringement.


Buy Now for $32.00

to gain full access to the content and tools.

Want to Subscribe?

Learn more about subscription options

Related Articles
Topic Collections
PubMed Articles
Forgot your password?
Enter your username and email address. We'll send you a reminder to the email address on record.