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Ubiquitin and proteasomes

Protein regulation by monoubiquitin

Key Points

  • Multi-ubiquitin chains target proteins for destruction by the proteasome. However, several proteins are monoubiquitylated. Recently, monoubiquitin has emerged as a regulator of the location and activity of diverse cellular proteins.

  • Histone regulation: Core histones H2A and H2B and the linker histone H1 are monoubiquitylated. Ubiquitylation of histones is important for gene expression during meiosis and development.

  • Endocytosis: Monoubiquitin serves as a signal to trigger the regulated internalization of plasma membrane proteins. Monoubiquitylation might also regulate the activity of components of the endocytic machinery.

  • Virus budding: The retrovirus Gag polyprotein is monoubiquitylated and this modification is required for late stages of virus budding from infected cells.

  • Surface regions of ubiquitin that are important for its different functions have been defined. One hydrophobic patch is promiscuous and is crucial for such diverse processes as proteasomal degradation and endocytosis. Another surface patch is important only for endocytosis and might have a role specifically in monoubiquitin functions.

  • Modification with monoubiquitin might regulate protein location and activity in ways that are similar to modification with the ubiquitin-like proteins, SUMO-1, Rub1 and Apg12.

  • Regulation of ubiquitin modification is important so that monoubiquitylated proteins are not inappropriately multi-ubiquitylated and degraded. Monoubiquitylation could be regulated by the activity of specific components of the ubiquitin machinery, by de-ubiquitylating enzymes, or by the presence or absence of positive and negative regulators of multi-ubiquitin chain assembly.

  • Many more monoubiquitin proteins probably exist and remain to be identified. The mechanism by which monoubiquitin regulates substrate protein location and activity is a mystery that is the next big challenge for researchers in the field.

Abstract

Multi-ubiquitin chains at least four subunits long are required for efficient recognition and degradation of ubiquitylated proteins by the proteasome, but other functions of ubiquitin have been discovered that do not involve the proteasome. Some proteins are modified by a single ubiquitin or short ubiquitin chains. Instead of sending proteins to their death through the proteasome, monoubiquitylation regulates processes that range from membrane transport to transcriptional regulation.

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Figure 1: Monoubiquitylation versus multi-ubiquitylation.
Figure 2: Monoubiquitylation of histones.
Figure 3: Roles of monoubiquitin during internalization of plasma membrane proteins into the endocytic pathway.
Figure 4: Monoubiquitylation of Gag is required for retrovirus budding.
Figure 5: Three-dimensional structure of ubiquitin.

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Acknowledgements

I thank R. Lamb, J. Widom, J. Wills and members of my lab for advice and helpful discussions, and R. Lamb and K. Lee for critical comments on the manuscript. J. Wills, H. Göttlinger, U. Schubert and J. Leis generously communicated unpublished results. I apologize to my colleagues whose work or references were not included owing to space restrictions.

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DATABASE LINKS

H2A

H2B

Rad6

H1

TAF250

Fat facets

epsin

Eps15

growth hormone receptor

Nedd4

AP2

Rpn10

Apg12

SCF ligase

Apg5

Apg8

SUMO-1

Rsp5

Rad23

FURTHER INFORMATION

Structure of monoubiquitin

Hicke lab

ENCYCLOPEDIA OF LIFE SCIENCES

Ubiquitin pathway

Lysosomal degradation of protein

Nucleosomes: detailed structure and mutations

Glossary

HISTONE

A family of small, highly conserved basic proteins, found in the chromatin of all eukaryotic cells, that associate with DNA to form a nucleosome.

ENDOCYTOSIS

Internalization and transport of extracellular material and plasma membrane proteins from the cell surface to intracellular organelles known as endosomes.

RETROVIRUS

RNA virus that uses reverse transcriptase to convert its RNA into DNA.

NUCLEOSOME

The basic structural subunit of chromatin, which consists of 200 base pairs of DNA and an octamer of histones.

SPORULATION

Sexual reproduction in yeast and fungi.

UBIQUITIN-CONJUGATING ENZYME (E2)

An enzyme that accepts ubiquitin from a ubiquitin-activating enzyme (E1) and, together with a ubiquitin ligase (E3), transfers it to a substrate protein.

TAF250

A subunit of TFIID, where TAF stands for TBP-associated factor, and TBP stands for TATA-box-binding protein.

TFIID

Transcription factor IID. A multisubunit general transcription factor, necessary for the transcription of all genes in eukaryotes.

LYSOSOME

A membrane-bounded organelle with a low internal pH (4?5) that contains hydrolytic enzymes and that is the site of the degradation of proteins in both the biosynthetic and the endocytic pathways.

EPS15

Epidermal growth factor receptor pathway substrate clone 15. Mammalian protein required for budding of clathrin-coated vesicles during endocytosis.

CLATHRIN

The main component of the coat that is associated with clathrin-coated vesicles, which are involved in membrane transport both in the endocytic and biosynthetic pathways.

DE-UBIQUITYLATING ENZYME

Enzyme that catalyses the cleavage of ubiquitin from multi-ubiquitin chains or protein conjugates.

GROWTH HORMONE RECEPTOR

A signal transducing receptor of the tyrosine-kinase family.

GAG

The protein of the nucleocapsid shell around the RNA of a retrovirus.

POLYPROTEIN

A single polypeptide chain that is cleaved into several separate proteins.

UBIQUITIN PROTEIN LIGASE (E3)

An enzyme that acts together with a ubiquitin-conjugating enzyme (E2) to couple the small protein ubiquitin to lysine residues on a target protein, marking that protein for destruction by the proteasome.

SCANNING ALANINE MUTAGENESIS

A method for determining the function of every residue in a protein sequence by mutating each one to alanine.

CULLIN

A family of proteins present in multisubunit ubiquitin ligases; they recruit RING-finger-containing proteins to the ligase complex.

SCF UBIQUITIN LIGASE

A multisubunit ubiquitin ligase that contains Skp1, a member of the cullin family (Cul1), and an F-box-containing protein (Skp2), as well as a RING-finger-containing protein (Roc1/Rbx1).

GATE-16

Protein with a ubiquitin fold, required for intra-Golgi transport and autophagy.

CHAPERONE

A protein that ensures the proper folding of other proteins.

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Hicke, L. Protein regulation by monoubiquitin . Nat Rev Mol Cell Biol 2, 195–201 (2001). https://doi.org/10.1038/35056583

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