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Ubiquitylation at the crossroads of development and disease

Key Points

  • Ubiquitylation is a post-translational modification that enables mechanistically diverse, quantitative and reversible regulation. Through controlling the stability, interactions or activity of important cellular regulators, ubiquitylation is essential for metazoan development.

  • Aberrant ubiquitylation, most frequently caused by mutation or aberrant expression of genes that encode E3 ubiquitin ligases or deubiquitinases, results in a wide range of developmental diseases, cancer or neurodegeneration.

  • Ubiquitin-dependent protein degradation coordinates proliferation of stem cell populations with the initiation of differentiation and cell fate specification.

  • Ubiquitylation of histone proteins, transcription regulators or ribosome biogenesis factors controls gene expression and mRNA translation programmes that are essential for differentiation.

  • Ubiquitin-dependent regulation of membrane proteins is crucial for cellular communication and cell migration during development.

  • Small molecules that target developmental ubiquitylation enzymes have emerged as a new approach to treating diseases, including cancer.

Abstract

Human development requires intricate cell specification and communication pathways that allow an embryo to generate and appropriately connect more than 200 different cell types. Key to the successful completion of this differentiation programme is the quantitative and reversible regulation of core signalling networks, and post-translational modification with ubiquitin provides embryos with an essential tool to accomplish this task. Instigated by E3 ligases and reversed by deubiquitylases, ubiquitylation controls many processes that are fundamental for development, such as cell division, fate specification and migration. As aberrant function or regulation of ubiquitylation enzymes is at the roots of developmental disorders, cancer, and neurodegeneration, modulating the activity of ubiquitylation enzymes is likely to provide strategies for therapeutic intervention.

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Figure 1: The ubiquitylation machinery.
Figure 2: Coordination of cell proliferation and differentiation.
Figure 3: Ubiquitin-dependent control of gene expression.
Figure 4: Ubiquitin-dependent control of mRNA translation and cell signalling.
Figure 5: Small-molecule regulation of E3 ligases implicated in developmental processes.

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Acknowledgements

The author apologizes to all colleagues whose work could not be cited owing to space constraints. The author is grateful to J. Schaletzky and all members of his laboratory for continued discussions, fresh ideas, and comments on this manuscript. The author's work is funded by grants from the National Institute of General Medical Sciences. M.R. is an Investigator with the Howard Hughes Medical Institute.

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M.R. is cofounder of and consultant to Nurix, a biotech company operating in the ubiquitin space.

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Glossary

Dendritic spines

Small protrusions from neuronal dendrites; each protrusion is typically connected to a single axon to receive signalling input.

WNT signals

The secreted glycoprotein WNT is often used as a signal to maintain pluripotency or regulate differentiation outcomes.

Planar cell polarity

Coordinated alignment of cell polarity across a tissue plane.

Haploinsufficiency

A condition when a protein product of both alleles is required for sustaining a normal phenotype.

RING

(Really interesting new gene). A signature domain of the largest class of E3 ligases.

Embryoid bodies

3D aggregates of pluripotent stem cells.

Opitz syndrome

A disease in which premature fusion of the metopic suture leads to a triangular shaped forehead.

CHARGE syndrome

A congenital disease that affects eye, nose and ear development.

Neural crest

A cell population that gives rise to melanocytes, cartilage, bone, smooth muscle, peripheral and enteric neurons, and glia.

Pseudouridylation

Isomerization of the uridine nucleoside in ribosomal RNA.

Small subunit (SSU) processome

A ribonucleoprotein complex involved in the processing, maturation and modification of the eukaryotic small ribosomal subunit.

Spemann organizer

A cell cluster in developing amphibian embryos that induces the formation of the central nervous system.

Paneth cells

Cell type in the stem cell niche of the small intestine.

Intestinal crypts

Region at the base of the intestinal epithelium that harbours the stem cells of this organ.

R-spondin proteins

Secreted WNT agonists.

Natural killer cells

Type of lymphocytes in the innate immune system.

Lateral inhibition

The ability of one cell to change the fate or inhibit differentiation of its neighbours.

Somitogenesis

Process of segment formation along the anterior–posterior axis of a developing embryo.

Epithelial–mesenchymal transition

Process by which epithelial cells lose their polarity and cell adhesion and gain migrational and mesenchymal properties.

Growth cones

Dynamic extensions at the tip of a growing axon.

Dentate gyrus

Part of the hippocampus that contributes to memory formation.

Homologous recombination

Genetic recombination between similar DNA molecules, often between sister chromatids during DNA damage repair.

DNA crosslink

A type of DNA damage, with nucleotides becoming covalently linked to each other.

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Rape, M. Ubiquitylation at the crossroads of development and disease. Nat Rev Mol Cell Biol 19, 59–70 (2018). https://doi.org/10.1038/nrm.2017.83

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