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Breaking the chains: deubiquitylating enzyme specificity begets function

Abstract

The deubiquitylating enzymes (DUBs, also known as deubiquitylases or deubiquitinases) maintain the dynamic state of the cellular ubiquitome by releasing conjugated ubiquitin from proteins. In light of the many cellular functions of ubiquitin, DUBs occupy key roles in almost all aspects of cell behaviour. Many DUBs show selectivity for particular ubiquitin linkage types or positions within ubiquitin chains. Others show chain-type promiscuity but can select a distinct palette of protein substrates via specific protein–protein interactions established through binding modules outside of the catalytic domain. The ubiquitin chain cleavage mode or chain linkage specificity has been related directly to biological functions. Examples include regulation of protein degradation and ubiquitin recycling by the proteasome, DNA repair pathways and innate immune signalling. DUB cleavage specificity is also being harnessed for analysis of ubiquitin chain architecture that is assembled on specific proteins. The recent development of highly specific DUB inhibitors heralds their emergence as a new class of therapeutic targets for numerous diseases.

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Change history

  • 19 February 2019

    Figure 2 of the article as originally published contained a graphic editing error, whereby the publisher’s redrawn figure wrongly indicated the presence of a Drosophila melanogaster orthologue of ZUP1. This has been corrected in the HTML and PDF versions of the manuscript.

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Acknowledgements

The authors thank J. Jardine for help with the preparation of original figures and K. Hofmann, D. Rigden, R. Damgaard and J. Morris for advice on sections of the manuscript.

Reviewer information

Nature Reviews Molecular Cell Biology thanks N. Mailand and other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information

M.J.C. wrote the manuscript with input from D.K. and S.U. S.U. prepared original figures. All authors read and discussed the manuscript and responded to reviewers.

Competing interests

The authors declare no conflicts of interest.

Correspondence to Michael J. Clague or Sylvie Urbé or David Komander.

Supplementary information

  1. Supplementary Tables

Glossary

SUMO

A family of ubiquitin-like proteins (SUMO1, SUMO2 and SUMO3) that can be attached to lysines of target proteins in a similar way to ubiquitin.

NEDD8

A ubiquitin-like protein that is conjugated to and activates a large family of ubiquitin E3 ligases: cullin–RING E3 ligases.

ISG15

A ubiquitin-like protein that is composed of two ubiquitin-like domains and is induced in response to interferon. ISG15 can be conjugated to proteins but also has activity in its unconjugated or even its secreted form.

Pseudoenzymes

Catalytically deficient variants of enzymes that exist in all major enzyme families.

COP9 signalosome

An eight-subunit protein complex that regulates protein ubiquitylation and turnover in various developmental and physiological contexts. Extensively characterized in plants but fundamental to all eukaryotes, this complex post-translationally modifies the cullin subunit of E3 ubiquitin ligases by cleaving off NEDD8.

Housekeeping functions

Basic or fundamental functions common to most cell types that maintain the broad cellular infrastructure.

Cullins

A family of scaffold proteins that constitute the backbone of a large superfamily of ubiquitin E3 ligases (cullin RING ligases (CRLs)).

Stress granules

Dense cytosolic assemblies or aggregates of ribosomal RNA and protein that accumulate in response to stress.

AAA-ATPases

A large superfamily of ATPases that regulate diverse processes in cells including disaggregation of proteins, protein degradation and membrane traffic.

APC/C

A large multiprotein ubiquitin E3 ligase complex that orchestrates cell cycle progression by promoting the proteasomal degradation of key cell cycle regulators.

Chromatin remodelling

Dynamic changes in the chromatin architecture that regulate access to DNA.

U4/U6.U5 triple small nuclear ribonucleoprotein

(U4/U6.U5 tri-snRNP). A major building block of the spliceosome comprising U4, U6 and U5 small nuclear RNAs (snRNAs) (with U4 and U6 strongly base paired) and >30 proteins.

Pulse–chase studies

Experiments that follow the fate of newly synthesized proteins over time by labelling proteins with radioactive isotope-containing or stable isotope-containing amino acids for a short time (pulse) followed by a chase with unlabelled amino acids.

Fanconi anaemia DNA crosslink repair

A DNA damage repair pathway that resolves DNA interstrand crosslinks and is executed by >20 proteins, for which loss of function is associated with Fanconi anaemia, a recessive disorder characterized by chromosomal instability and hypersensitivity to agents that induce DNA crosslinks.

Translesion synthesis repair

An error-prone DNA damage repair process that allows DNA replication to proceed past lesions such as thymidine dimers or abasic sites using specialized DNA polymerases.

γ-H2AX

A histone H2AX variant that is phosphorylated on Ser139 and accumulates rapidly in response to double-stranded DNA damage.

Linker histone H1

A histone that binds to the linker DNA in-between nucleosomes, which are themselves composed of an octamer of histones H2A, H2B, H3 and H4.

Non-homologous end joining

(NHEJ). A DNA damage repair pathway that does not rely on the presence of a homologous template, in contrast to homology-directed repair.

Homology-directed repair

(HDR). A mechanism of double-strand DNA damage repair that relies on a homologous template and thus is restricted to the G2 and S phases of the cell cycle.

Replication stress

Stress occurring during genome replication, a major cause of genome instability.

Micronuclei

Extranuclear bodies containing chromosomes or fragments thereof that escaped incorporation into the nucleus during cell division.

NF-κB signalling pathway

An innate immune signalling pathway that results in the activation of the transcription factor nuclear factor-κB (NF-κB).

Pattern recognition receptors

Receptors including Toll-like receptors and NOD that recognize conserved molecular structures (pathogen-associated molecular patterns and damage-associated molecular patterns) that are found in pathogens (bacteria, viruses, fungi and parasites).

Endosomal sorting complex required for transport

(ESCRT). A multimeric protein complex that was first identified biochemically in yeast. One function of the ESCRT machinery is to control the sorting of endosomal cargo proteins into internal vesicles of multivesicular bodies.

Microcephaly capillary malformation syndrome

(MIC-CAP). An inherited (congenital) disorder characterized by an abnormally small head and aberrant capillaries in the skin.

Cushing disease

A collection of symptoms caused by prolonged exposure to high levels of cortisol in the blood, most commonly caused by a benign tumour of the pituitary gland (resulting in increased levels of adrenocorticotropic hormone release and stimulation of cortisol production in the adrenal gland).

Securin

A key mitotic substrate of APC/C that needs to be degraded to allow the segregation of sister chromatids during anaphase.

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Fig. 1: Major roles of DUBs.
Fig. 2: Phylogenetic conservation of DUBs.
Fig. 3: Subcellular localization of DUBs in mammalian cells.
Fig. 4: Essential DUBs.
Fig. 5: DUBs implicated in the DNA damage response at double-strand breaks.
Fig. 6: Chain-specific DUBs orchestrate innate immune signalling.