Review
The Ubiquitin Code in the Ubiquitin-Proteasome System and Autophagy

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Monoubiquitination has been thought to be non-proteolytic and regulate the interactions and activities of substrates. Emerging evidence shows that monoubiquitin(s) of substrates functions as the degron in the UPS and autophagy.

Atypical linkages such as Lys11 and Lys29 linkages serve as proteasomal degrons, alone or in combination with other linkages such as Lys48 and/or Lys63.

Ubiquitin chains such as Lys63 linkages mediate autophagic protein quality control through the recognition by autophagic adaptors such as p62.

Ubiquitin chains, mainly Lys63 linkages, function as a trans-degron for autophagic removal of cellular organelles and structures in mitophagy, pexophagy, ER-phagy, ribophagy, and lipophagy.

Ubiquitin is the substrate of small-molecule post-translational modifications such as phosphorylation and acetylation.

The conjugation of the 76 amino acid protein ubiquitin to other proteins can alter the metabolic stability or non-proteolytic functions of the substrate. Once attached to a substrate (monoubiquitination), ubiquitin can itself be ubiquitinated on any of its seven lysine (Lys) residues or its N-terminal methionine (Met1). A single ubiquitin polymer may contain mixed linkages and/or two or more branches. In addition, ubiquitin can be conjugated with ubiquitin-like modifiers such as SUMO or small molecules such as phosphate. The diverse ways to assemble ubiquitin chains provide countless means to modulate biological processes. We overview here the complexity of the ubiquitin code, with an emphasis on the emerging role of linkage-specific degradation signals (degrons) in the ubiquitin-proteasome system (UPS) and the autophagy-lysosome system (hereafter autophagy).

Section snippets

Ubiquitin-Based Degrons in Cellular Degradative Pathways

Eukaryotic cells operate two major proteolytic systems: the UPS and autophagy. The UPS is a selective proteolytic system in which the conjugation of ubiquitin to substrates induces degradation by the proteasome 1, 2, 3. Autophagy is a process by which cytoplasmic constituents are degraded by the lysosome [4]. This bulk degradative system can be divided into microautophagy, chaperone-mediated autophagy, and macroautophagy, depending on the mechanism of cargo delivery to the lysosome. The UPS and

Overview of the Ubiquitin Code

The simplest type of ubiquitination is monoubiquitination, which often occurs at multiple Lys residues (multi-monoubiquitination) [18] (Figure 1). Monoubiquitination has been long thought to be non-proteolytic and acts as a phosphorylation-like modification that regulates the interactions and activities of substrates. However, emerging evidence shows that monoubiquitination produces a proteasomal degron which is much stronger and general than previously thought [19]. Following

Monoubiquitination Reborn as a Proteasomal and Autophagic Degron

The paradigm in the UPS has been that monoubiquitination modulates the activity, trafficking, and interaction of substrates in non-degradative processes. The substrates of monoubiquitination include histone H2A (up to 10% of the total H2A population) and various regulators in the endocytic pathway such as Eps15 [18]. This paradigm has not been challenged despite several isolated studies reporting that monoubiquitination (or multi-monoubiquitination) can induce degradation of several short-lived

Polyubiquitin Chains in Proteolysis via the UPS

Lys48 polyubiquitin is the most abundant linkage and generates a degron that induces proteasomal proteolysis [1] (Figure 2). Lys48 polymers are bound by the UBDs of specific receptors such as RPN10, RPN13, RAD23, and UBQLNs 7, 47. Extensive studies over the past few decades showed that proteasomal degradation based on Lys48 linkages target a large number of cellular proteins (estimated to exceed 5000), regulating virtually all biological processes including cell division, transcription,

Polyubiquitin Chains in Autophagic Proteolysis

In protein quality control, soluble misfolded proteins are tagged with mainly Lys48-linked polyubiquitin by a set of E3 ligases such as UBR1, UBR2, parkin, C terminus of Hsc70-interacting protein (CHIP), San1, E6-AP, and Hul5 [3] (Figure 3). The ubiquitin chains are bound by the UBDs of proteasome-associated receptors such as RPN10 and RPN13 for proteasomal degradation. When terminally misfolded proteins escape from proteasomal degradation, those ubiquitin-tagged substrates (mostly

Polyubiquitin Chains in the Lysosomal Removal of Non-Proteinaceous Cellular Constituents

There is a general notion that Lys63-linked ubiquitin chains are not ‘degrons’ for normally folded short-lived proteins, and instead modulate non-proteolytic processes such as the DNA damage response and immune signaling pathways. This is correct under the scope of fast and selective degradation by the proteasome, but not when extended to slow and bulk degradation by the lysosome. Moreover, recent studies suggest that Lys63-linked ubiquitin chains, most likely in collaboration with other

Polyubiquitin Chains in Non-Proteolytic Processes

Recent advances in mass spectrometry using ubiquitin linkage-specific antibodies made it possible to measure the relative abundance and functions of atypical Lys linkages (Lys6, Lys11, Lys27, Lys29, and Lys33) [15]. In addition to proteolytic processes as described above, these atypical linkages mediate various non-proteolytic processes such as trafficking, signaling, and autophagy 96, 97. Overall, Lys27 linkages generate molecular beacons that interact with the UBDs of other proteins in the

Concluding Remarks

Ubiquitination was originally thought to target only a few substrates, with limited physiological importance. This post-translational modification is now appreciated to be much more complicated. The discoveries of multilayer complexity in ubiquitin linkages and their modifications, such as SUMOylation and phosphorylation, provide countless means to modulate almost all known biological processes. The primary function of ubiquitination is to generate degrons on short-lived proteins and

Acknowledgments

We thank Ho Sun Kim for editorial assistance, Jung Woo Hwang for graphic design, and Sang Mi Shim, Sung Tae Kim, and other laboratory members for critical discussions while preparing the manuscript. Research in the laboratory of A.C. is supported by grants from the Dr Miriam and Sheldon G. Adelson Medical Research Foundation (AMRF), the Israel Science Foundation (ISF), the I-CORE Program of the Planning and Budgeting Committee, the ISF (grant 1775/12), the Deutsch-Israelische Projektkooperation

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