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The spatial and temporal organization of ubiquitin networks

Nature Reviews Molecular Cell Biology volume 12, pages 295–307 (2011)Cite this article

Subjects

Key Points

  • Ubiquitylation is mediated by the sequential activity of activating (E1), conjugating (E2) and ligating (E3) enzymes, resulting in the conjugation of monoubiquitin or polyubiquitin chains of different length and linkages to target proteins. Ubiquitin signals are decoded by ubiquitin receptors containing ubiquitin-binding domains (UBDs).

  • The ubiquitin network is strictly regulated in a spatiotemporal manner. Compartmentalization of ubiquitin-conjugation machinery proteins, deubiquitylating enzymes (DUBs) and downstream effectors, as well as sequential series of ubiquitylation events, are common strategies to confer spatial and temporal hierarchy to ubiquitylation.

  • Subcellular targeting of ubiquitin network components can be promoted by transmembrane anchors, nuclear localization signals, binding to scaffold proteins or reorganizations induced by other post-translational modifications. Coupled monoubiquitylation is also frequently used to control the activity and localization of proteins.

  • The nuclear factor-κB (NF-κB) pathway is regulated by many ubiquitin species, including Lys11-, Lys48- and Lys63-linked chains, as well as linear chains of different lengths. These function to spatially and temporally reorganize kinase complex activation in distinct branches of the pathway.

  • Ubiquitylation is a key determinant for spatial coordination of DNA repair and for the sorting and trafficking of membrane proteins by endosomal sorting complex required for transport (ESCRT)-associated proteins along the endocytic pathway. Ubiquitylation is also crucial for protein turnover in the ubiquitin–proteasome system, endoplasmic reticulum-associated degradation (ERAD) and autophagosomal pathways.

  • Spatial organization of ubiquitin-conjugating proteins and their regulators is crucial for pattern formation in the early development of many species, as well as during the specification and functional adaptation of individual cell and tissue types, in particular the nervous system.

Abstract

In the past decade, the diversity of signals generated by the ubiquitin system has emerged as a dominant regulator of biological processes and propagation of information in the eukaryotic cell. A wealth of information has been gained about the crucial role of spatial and temporal regulation of ubiquitin species of different lengths and linkages in the nuclear factor-κB (NF-κB) pathway, endocytic trafficking, protein degradation and DNA repair. This spatiotemporal regulation is achieved through sophisticated mechanisms of compartmentalization and sequential series of ubiquitylation events and signal decoding, which control diverse biological processes not only in the cell but also during the development of tissues and entire organisms.

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Figure 1: Ubiquitylation — bringing temporal and spatial order to the NF-κB pathway.
Figure 2: Ubiquitin-mediated coordination of receptor endocytosis.
Figure 3: Polarized functions of ubiquitylation in neurons.
Figure 4: Control of development by localized ubiquitylation events.

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Acknowledgements

We apologize to all scientists whose important contributions were not referenced in this Review owing to limitations in the number of references. We are grateful to C. Joazeiro and H. Walczak for comments and discussions. C.G. is supported by the Swedish Foundation for Strategic Research (SSF). Research in the I.D. laboratory is supported by the Deutsche Forschungsgemeinschaft, the Cluster of Excellence 'Macromolecular Complexes' of the Goethe University Frankfurt (EXC115) and a European Research Council Advanced Grant.

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Authors and Affiliations

  1. Department of Molecular Biology, Ume University, Building 6L, SE-901 87, Umeå, Sweden

    Caroline Grabbe

  2. Frankfurt Institute for Molecular Life Sciences and Institute of Biochemistry II, Goethe University School of Medicine, Theodor-Stern-Kai 7, Frankfurt (Main), D-60590, Germany

    Koraljka Husnjak & Ivan Dikic

  3. Department of Immunology, School of Medicine, University of Split, Soltanska 2, Split, 21000, Croatia

    Ivan Dikic

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  1. Caroline Grabbe
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Correspondence to Ivan Dikic.

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Glossary

RING

A zinc-binding protein–protein interaction motif, found in RING-type ubiquitin E3 ligases, that binds to the E2 ubiquitin thioester and thereby promotes ubiquitin transfer to substrate proteins.

ER-associated degradation

A protein quality control pathway (mediated by p97–VCP–CDC48) in which misfolded or regulated proteins residing in the endoplasmic reticulum (ER) are translocated into the cytosol for proteasomal degradation.

Ubiquitin-like molecule

A protein that structurally resembles ubiquitin and uses its own E1, E2 and E3 enzymes to conjugate to target proteins and to modify their properties. Examples are the small ubiquitin-like modifiers (SUMOs), NEDD8, ISG15, Fat10 and autophagy-related 8.

N-end rule

A biological principle that relates the half-life of a cellular protein to the identity of its amino-terminal residue, in which N-terminal amino acids are recognized by specific E3 ubiquitin ligases (N-recognins).

Breast cancer type 1 susceptibility

(BRCA1). An E3 ligase that catalyses multiple types of ubiquitin signals. It is often found in a heterodimeric RING complex with BRCA1-associated RING domain 1 and has an important role in homologous recombination repair of DNA double-strand breaks.

Ubiquitin-interacting motif

An α-helical ubiquitin-binding domain that binds to the conserved hydrophobic patch that is centred around Ile44 in ubiquitin with an affinity in the range of ∼100–400M.

HECT

One of the major classes of ubiquitin ligases. HECT E3 ligases contain a domain with a catalytic Cys residue that forms a thioester intermediate during ubiquitin transfer to the substrate protein.

Proliferating cell nuclear antigen

(PCNA). A ring-shaped molecule encircling DNA. It slides bidirectionally along DNA to constitutively monitor genomic integrity. Following DNA damage, ubiquitylation of PCNA is essential for the recruitment of damage-tolerant DNA polymerases, allowing translesion synthesis.

F-box

A protein module of ∼50 residues that is involved in mediating protein–protein interactions. F–box proteins commonly act as substrate recognition subunits in cullin–RING ubiquitin ligases.

Receptor Tyr kinase

A membrane-bound protein Tyr kinase that often functions as a receptor for secreted hormones, growth factors and cytokines.

Diubiquitin motif

A double-sided ubiquitin-binding domain, first identified in hepatocyte growth factor-regulated Tyr kinase substrate (HRS), that can simultaneously bind two ubiquitin moieties, both of which are required for the endocytic sorting function of HRS.

GRAM-like ubiquitin-binding in EAP45

A ubiquitin-binding domain that folds into a split pleckstrin homology domain with a non-canonical lipid-binding pocket that interacts with phosphatidylinositol-3-phosphate.

Multivesicular body

(MVB). An intermediate structure in the endosomal pathway that is formed when membrane portions bud into the lumen of late endosomes, forming intralumenal vesicles. MVB sorting is an essential event for the degradation of internalized cell surface proteins in the lysosome.

Ubiquitin-associated domain

A short (∼40 amino acids) sequence motif, first found in proteins associated with the ubiquitylation pathway, that mediates polyubiquitin binding.

Ubiquitin-like domain

(UBL domain). A modular protein domain present in multiple cellular proteins. UBL domains structurally resemble ubiquitin by folding into the ubiquitin β-grasp superfold and can in general be recognized by ubiquitin-binding domains.

JAMM

(JAB1/MPN/MOV34 metalloenzyme). A family of zinc metalloprotease deubiquitylating enzymes.

Anaphase-promoting complex

A multifunctional ubiquitin ligase that, by pairing with its co-activators CDC20 and CDH1, specifically targets cell cycle proteins (among others) for degradation.

Cullin–RING ubiquitin ligase

(CRL). A member of a large family of multisubunit E3 ligases, commonly comprising a cullin scaffold, a catalytic RING subunit, a substrate-recognition subunit (SRS), and, for most CRLs, an adaptor subunit linking the SRS to the complex.

Postsynaptic density

(PSD). A structure in the postsynaptic membrane in which LGlu neurotransmitter receptors are accumulated together with multiple adhesion, scaffold, cytoskeletal and signalling molecules. PSDs organize the postsynaptic signalling machinery, control synaptic plasticity and maintain synaptic homeostasis.

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Grabbe, C., Husnjak, K. & Dikic, I. The spatial and temporal organization of ubiquitin networks. Nat Rev Mol Cell Biol 12, 295–307 (2011). https://doi.org/10.1038/nrm3099

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