Elsevier

Gene

Volume 248, Issues 1–2, 2 May 2000, Pages 1-14
Gene

Review
Ubiquitin-like proteins: new wines in new bottles

https://doi.org/10.1016/S0378-1119(00)00139-6Get rights and content

Abstract

Ubiquitin is a small polypeptide that covalently modifies other cellular proteins and targets them to the proteasome for degradation. In recent years, ubiquitin-dependent proteolysis has been demonstrated to play a critical role in the regulation of many cellular processes, such as cell cycle progression, cell signaling, and immune recognition. The recent discovery of three new ubiquitin-like proteins, NEDD8, Sentrin/SUMO, and Apg12, has further broadened the horizon of this type of post-translational protein modification. This review will focus on the biology and biochemistry of the Sentrin/SUMO and NEDD8 modification pathways, which are clearly distinct from the ubiquitination pathway and have unique biological functions.

Introduction

Since the identification of ubiquitin as the heat-stable factor in an ATP-dependent proteolysis assay two decades ago, tremendous strides have been made in our understanding of the biology and biochemistry of ubiquitination (Ciechanover, 1998, Hershko and Ciechanover, 1998). A ubiquitin-like protein, UCRP/ISG15, which contains two ubiquitin-like domains in tandem, was reported in 1987 (Haas et al., 1987, Loeb and Haas, 1992). Additional ubiquitin-like sequences have also been reported over the years (Biggins et al., 1996, Michiels et al., 1993, Schauber et al., 1998); however, only ubiquitin and UCRP/ISG15 were shown to possess the ability to covalently modify other cellular proteins. The field changed dramatically in 1996 with the discovery of a novel ubiquitin-like protein modifier, Sentrin-1 (also called SUMO-1, PIC-1, GMP-1, UBL1, SMT3C), by several laboratories (Boddy et al., 1996, Kamitani et al., 1997a, Lapenta et al., 1997, Mahajan et al., 1997, Mannen et al., 1996, Matunis et al., 1996, Okura et al., 1996, Shen et al., 1996b, Tsytsykova et al., 1998). In 1997, another novel ubiquitin-like protein, NEDD8, was shown to define yet another protein modification pathway (Kamitani et al., 1997a). Finally, Apg12 was found to represent the fourth ubiquitin-like protein modification pathway required for autophagy (Mizushima et al., 1998a, Mizushima et al., 1998b). The discoveries of these novel proteins have sparked tremendous interest in ubiquitin-like protein modification pathways. This review will focus exclusively on the biology and biochemistry of Sentrin and NEDD8 modification pathways. Similarity in the enzymatic mechanism between ubiquitin and ubiquitin-like modification will be contrasted with the richness in functional diversity of these pathways.

Section snippets

Ubiquitination

Ubiquitin is a 76 amino acid polypeptide, which is highly conserved in evolution with only three amino acid differences between the human and yeast homologues. The C-terminus of ubiquitin contains a conserved Gly residue, which is activated in an ATP-dependent manner to form a thiol ester linkage with the cysteine residue of the ubiquitin-activating enzyme (E1) (Haas and Siepmann, 1997) (Fig. 1). Activated ubiquitin is then transferred to a carrier protein (E2) to form another thiol ester

Sentrin family of ubiquitin-like proteins

The Sentrin family of ubiquitin-like proteins consists of Sentrin-1, Sentrin-2, and Sentrin-3. Sentrin-1 is a 101 amino acid protein containing a ubiquitin-homology domain (residues 22–97), which is 18% identical and 48% homologous to human ubiquitin (see Fig. 2). Sentrin-2 is a 95 amino acid polypeptide, which is 46% identical and 66% similar to Sentrin-1 in the ubiquitin-homology domain. Sentrin-3 is a 103 amino acid polypeptide, which is 97% identical to Sentrin-2 in the ubiquitin-homology

NEDD8 and Rub1

NEDD8 (neural precursor cell-expressed developmentally downregulated) was originally reported as a novel mRNA highly enriched in fetal mouse brain (Kumar et al., 1992). Northern blot analysis showed that the NEDD8 message was developmentally downregulated (Kamitani et al., 1997a). In adult tissues NEDD8 expression was mostly restricted to the heart and skeletal muscle. Antiserum specific for NEDD8 detected a 6 kDa NEDD8 monomer, and a series of higher molecular weight NEDD8-conjugated proteins

Conclusions

In this review, we concisely summarized our current understanding of two novel ubiquitin-like proteins. It is clear that the sentrinization and NEDD8 modification define two enzymatic pathways distinct from ubiquitination. Nonetheless, the enzymatic principles, such as activation, conjugation, and ligation, appear to be conserved among these pathways. NEDD8 is structurally more related to the ubiquitin and the NEDD8 modification pathway appears to play an important role in ubiquitin-mediated

Acknowledgements

This work was supported in part by the Institute of Molecular Medicine for the Prevention of Human Diseases, Grants from the National Institutes of Health, the DREAM Project, American Heart Association, and Arthritis Foundation.

References (124)

  • L. Gong et al.

    Identification of the activating and conjugating enzyme of the NEDD conjugation pathway

    J. Biol. Chem.

    (1999)
  • L. Gong et al.

    Preferential interaction of sentrin with a ubiquitin-conjugating enzyme, Ubc9

    J. Biol. Chem.

    (1997)
  • L. Gong et al.

    Molecular cloning and characterization of human AOS1 and UBA2, components of the sentrin-activating enzyme complex

    FEBS Lett.

    (1999)
  • L. Gong et al.

    Differential regulation of sentrinized proteins by a sentrin-specific protease

    J. Biol. Chem.

    (2000)
  • M. Gottlicher et al.

    Interaction of the Ubc9 human homologue with c-Jun and with the glucocorticoid receptor

    Steroids

    (1996)
  • A.L. Haas et al.

    Interferon induces a 15-kilodalton protein exhibiting marked homology to ubiquitin

    J. Biol. Chem.

    (1987)
  • G. Hateboer et al.

    mUBC9, a novel adenovirus E1A-interacting protein that complements a yeast cell cycle defect

    J. Biol. Chem.

    (1996)
  • G.S. Huggins et al.

    Characterization of the mUBC9-binding sites required for E2A protein degradation

    J. Biol. Chem.

    (1999)
  • D.R. Joanisse et al.

    Cloning and developmental expression of a nuclear ubiquitin-conjugating enzyme (DmUbc9) that interacts with small heat shock proteins in Drosophila melanogaster

    Biochem. Biophys. Res. Commun.

    (1998)
  • E.S. Johnson et al.

    Ubc9p is the conjugating enzyme for the ubiquitin-like protein, Smt3p

    J. Biol. Chem.

    (1997)
  • T. Kamitani et al.

    Characterization of NEDD8, a developmentally downregulated ubiquitin-like molecule

    J. Biol. Chem.

    (1997)
  • T. Kamitani et al.

    Preferential modification of nuclear proteins by a novel ubiquitin-like molecule

    J. Biol. Chem.

    (1997)
  • T. Kamitani et al.

    Characterization of a second member of the sentrin family of ubiquitin-like proteins

    J. Biol. Chem.

    (1998)
  • T. Kamitani et al.

    Identification of three major sentrinization sites in PML

    J. Biol. Chem.

    (1998)
  • T. Kamitani et al.

    Covalent modification of PML by the sentrin family of ubiquitin-like proteins

    J. Biol. Chem.

    (1998)
  • Y.H. Kim et al.

    Homeodomain-interacting protein kinases, a novel family of co-repressors for homeodomain transcription factors

    J. Biol. Chem.

    (1998)
  • E.T. Kipreos et al.

    cul-1 is required for cell cycle exit in C. elegans and identifies a novel gene family

    Cell

    (1996)
  • S. Kumar et al.

    Identification of a set of genes with developmentally downregulated expression in the mouse brain

    Biochem. Biophys. Res. Commun.

    (1992)
  • J.D. Laney et al.

    Substrate targeting in the ubiquitin system

    Cell

    (1999)
  • V. Lapenta et al.

    SMT3A, a human homologue of the S. cerevisiae SMT3 gene, maps to chromosome 21qter and defines a novel gene family

    Genomics

    (1997)
  • G.W. Lee et al.

    Modification of ran GTPase-activating protein by the small ubiquitin-related modifier SUMO-1 requires Ubc9, an E2-type ubiquitin-conjugating enzyme homologue

    J. Biol. Chem.

    (1998)
  • Q. Liu et al.

    The binding interface between an E2 (UBC9) and a ubiquitin homologue (UBL1)

    J. Biol. Chem.

    (1999)
  • K.R. Loeb et al.

    The interferon-inducible 15-kDa ubiquitin homolog conjugates to intracellular proteins

    J. Biol. Chem.

    (1992)
  • D.A. Loveys et al.

    The mUBC9 murine ubiquitin conjugating enzyme interacts with the E2A transcription factors

    Gene

    (1997)
  • R. Mahajan et al.

    A small ubiquitin-related polypeptide involved in targeting RanGAP1 to nuclear pore complex protein RanBP2

    Cell

    (1997)
  • H. Mannen et al.

    Cloning and expression of human homolog HSMT3 to yeast SMT3 suppressor of MIF2 mutations in a centromere protein gene

    Biochem. Biophys. Res. Commun.

    (1996)
  • M. Masson et al.

    Poly(ADP-ribose) polymerase interacts with a novel human ubiquitin conjugating enzyme: hUbc9

    Gene

    (1997)
  • M.J. May et al.

    Signal transdcution through NFκB

    Immunol. Today

    (1998)
  • A. Melnick et al.

    Deconstructing a disease: RARalpha, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia

    Blood

    (1999)
  • T. Ohta et al.

    ROC1, a homolog of APC11, represents a family of cullin partners with an associated ubiquitin ligase activity

    Mol. Cell

    (1999)
  • T. Okuma et al.

    In vitro SUMO-1 modification requires two enzymatic steps, E1 and E2

    Biochem. Biophys. Res. Commun.

    (1999)
  • H. Poukka et al.

    Ubc9 interacts with the androgen receptor and activates receptor-dependent transcription

    J. Biol. Chem.

    (1999)
  • C. Rao-Naik et al.

    The rub family of ubiquitin-like proteins — crystal structure of arabidopsis rub1 and expression of multiple rubs in arabidopsis

    J. Biol. Chem.

    (1998)
  • H. Saitoh et al.

    Functional heterogeneity of small ubiquitin-related modifers, SUMO-1 versus SUMO2/3

    J. Biol. Chem.

    (2000)
  • H. Saitoh et al.

    Ubc9p and the conjugation of SUMO-1 to RanGAP1 and RanBP2

    Curr. Biol.

    (1998)
  • A. Saltzman et al.

    hUBC9 associates with MEKK1 and type I TNF-alpha receptor and stimulates NFkappaB activity

    FEBS Lett.

    (1998)
  • S. Biggins et al.

    Yeast ubiquitin-like genes are involved in duplication of the microtubule organizing center

    J. Cell Biol.

    (1996)
  • R.F. Bischoff et al.

    Human RanGTPase-activating protein RanGAP1 is a homologue of yeast Rna1p involved in mRNA processing and transport

    Proc. Natl. Acad. Sci. USA

    (1995)
  • M.N. Boddy et al.

    PIC 1, a novel ubiquitin-like protein which interacts with the PML component of a multiprotein complex that is disrupted in acute promyelocytic leukaemia

    Oncogene

    (1996)
  • S.R. Chakrabarti et al.

    Modulation of TEL transcription activity by interaction with the ubiquitin-conjugating enzyme UBC9

    Proc. Natl. Acad. Sci. USA

    (1999)
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