Role of ubiquitin- and Ubl-binding proteins in cell signaling

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Besides tagging proteins for degradation, ubiquitin is now recognized as a signaling module for diverse cellular processes, including progression through the cell cycle, DNA repair, gene transcription, receptor trafficking and endocytosis. Recent advances have indicated the existence of a wide variety of ubiquitin-binding proteins that, upon recognition of conjugated ubiquitin moieties, can control assembly of complex signaling networks. Small ubiquitin-like proteins, like SUMO, emerge to play biological roles distinct from ubiquitin, and require specific recognition by a dedicated set of proteins. Identification and characterization of recognition motifs and domains for ubiquitin-like proteins have just begun, promising new insights into the diversity of functions ubiquitin family proteins have in physiological and pathological settings.

Introduction

Ubiquitin (Ub) is a small versatile protein that has been a focus of active research during the past 30 years. Once freed from its precursor polypeptide by specific proteases, it is subjected to an enzymatic reaction cascade, which involves Ub-activating (E1), Ub-conjugating (E2) and Ub-ligating (E3) enzymes. This ultimately leads to the covalent attachment of Ub to a lysine (K) residue or the N-terminus of the target protein, referred to as ubiquitylation, or ubiquitination [1]. Through repeated conjugation to itself, Ub can form long chains that, in the case of K48-linkage, constitute a well-recognized proteasomal degradation signal [1]. Alternative Ub chain formation appears to play other important regulatory roles (e.g. K63-linkage in NF-κB signaling [2]). As well as forming polyubiquitin (polyUb) chains, single Ub moieties (monoUb) can also be covalently attached to various proteins. Monoubiquitylation has now surfaced as a major signaling event thought to mediate complex cellular processes, of which endocytosis and DNA repair are the best-studied examples [2]. The ability of different Ub chains and monoUb to signal in different ways seems to depend largely on the specificity and function of proteins that serve as Ub receptors. Ub-binding modules found within these proteins have co-evolved with Ub to recognize and bind their ligand, thereby mediating all known functions of Ub. So far >15 individual ubiquitin binding domains (UBDs) have been identified ([3, 4] and references therein) and this number is constantly growing (Table 1).

Besides Ub, 13 other small Ub-like protein modifiers (Ubls) have been described to date (Table 1). All of them share a characteristic β-grasp fold (the ‘ubiquitin fold’) and can be conjugated to proteins or lipids via their C-terminus [5, 6]. Attachment of Ubls to their substrate has been shown to have profound influence on various cellular processes, including transcription, DNA repair, signal transduction and autophagy [6]. By analogy to Ub, recognition of Ubls by specialized protein domains is predicted to drive these cellular responses. Indeed, recent results provide several examples of such novel recognition modules. This review covers major advances made in the last two years in understanding how Ub- and Ubl-binding proteins mediate and control cellular signaling networks.

Section snippets

Ub-binding proteins in proteolysis

The first recognized function of Ub was earmarking proteins for the proteasomal degradation pathway. Consequently, the first Ub-binding protein to be published was a proteasome subunit S5A/RPN10 [7]. In the meantime it has become quite clear that the few constitutive proteasome receptors do receive generous donations from multiple adaptors, such as yeast proteins rad23p and Dsk2p. They possess both UBDs and Ub-like (UBL) domains and, through binding both Ub and the proteasome, dock

Ubiquitin-binding proteins in endocytosis

The majority of cell-surface receptors undergo endocytosis either constitutively or as a result of their activation. Conjugation with monoUb [13] or oligo-Ub chains [14] functions as an endosomal sorting signal for receptor tyrosine kinases (RTKs), G-protein-coupled receptors (GPCRs), transporters and ion channels [15, 16]. Elaborate molecular machinery is responsible for recognition and sorting of monoubiquitylated cargo from the cell membrane and, further along the endocytic route, for

Ub signaling in transcription and DNA repair

Gene transcription is a fundamental process whose regulation is the end point of many signaling pathways in the cell. Given the fact that histones were the first published substrate for Ub-conjugation, the role of Ub in chromatin regulation has long been suggested. Today it is largely believed that monoubiquitylation is able to influence transcription by causing changes in the other post-translational modifications of histones, such as methylation and acetylation, and hence altering chromatin

Signaling role of SUMO-binding proteins

Modification of proteins with SUMO has long been known to regulate various cellular processes, such as nuclear transport, cell cycle, transcription and DNA repair [40]. In a great number of cases, however, the exact mechanism by which sumoylation is translated into a biological effect is unknown. However, by analogy to Ub, it is safe to speculate that SUMO-binding proteins will act as sensors for this modification, thereby providing the basis for protein–protein interaction platforms. Indeed,

Conclusions and perspectives

Characterization of non-covalent interactions between Ub and Ub-binding proteins using both biochemical and structural analyses has provided an important insight into the mechanistic link between ubiquitylation and the processes it regulates. The variety and specificity of cellular responses to Ub can now be attributed to the diversity of UBD-containing proteins, each of which displays a unique binding repertoire. Although UBD–Ub interactions are typically weak (Kd>50 μM [4]), the latest

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We are thankful to Kaisa Haglund and Daniela Hoeller for critical comments on the manuscript. We apologize to investigators whose important contributions were not included in this review due to space limitations. I.D. acknowledges support from the Deutsche Forschungsgemeinschaft, the German-Israeli Foundation and the Boehringer Ingelheim Foundation.

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