Trends in Biochemical Sciences
ReviewActivating the ubiquitin family: UBA6 challenges the field
Section snippets
The ubiquitin family
The post-translational modification of proteins by phosphate, sugars or lipids has long been recognized as a means to alter the properties of proteins. When the ATP-dependent degradation of proteins was first investigated nearly three decades ago, it became clear that the scope of protein modifications extends to the covalent linkage with a 76-residue polypeptide termed ubiquitin 1, 2. The ubiquitin C terminus becomes isopeptide-linked to the ɛ-amino group of lysines within target proteins.
Structure and enzymatic mechanisms of E1 enzymes
To date, eight E1 enzymes have been identified owing to their conserved three-domain structure, and most have been assigned to one of the known ULMs (Table 1). E1 enzymes are either formed by a single polypeptide chain or are heterodimers such as the E1 enzymes AOS1–UBA2 and β-amyloid precursor protein-binding protein (APP-BP)-1–UBA3 for SUMO1–3 and NEDD8, respectively, which carry the characteristic E1 domains on two separate polypeptides 18, 19. One task of E1 enzymes is to bind noncovalently
UBA6: a second ubiquitin-activating enzyme
An E1 enzyme that activates ubiquitin was initially described, characterized and purified in 1981 and 1982 20, 28, 29; corresponding genes, named UBA1 in yeast and plants and UBE1 in mammals, were cloned a decade later 30, 31, 32, 33. In Saccharomyces cerevisiae, UBA1 is essential, indicating that no other E1-type enzyme can compensate for this deficiency. In mammals, UBE1 is encoded on the X chromosome, which explains how mutations in the single copy of UBE1 generated several
UBA6 activates two different modifiers: ubiquitin and FAT10
UBA6 challenges a second major paradigm in the ubiquitin field – namely, that a specific E1 enzyme only activates one type or one closely related subfamily of modifiers. Thoroughly investigated examples for this selectivity are NEDD8 and ubiquitin, which are nearly 60% identical; a single arginine residue in the E1 for NEDD8 determines its selectivity for NEDD8 and prevents aberrant ubiquitin activation [46]. By contrast, UBA6 was recently shown to activate two ubiquitin family proteins,
Concluding remarks and future perspectives
The unique properties of UBA6 challenge two major paradigms of ULM conjugation: first, UBE1 and UBA6 are the first examples of E1 enzymes that both activate the same member of the ULM family, and, second, UBA6 is, aside from ATG7 and AOS1–UBA2, the third example of an E1 that activates two ULMs: ubiquitin and FAT10, which have widely different structural and biological properties. Because UBE1 and UBA6 cooperate with only partially overlapping pools of E2 enzymes 16, 17, it is expected that at
Acknowledgements
We thank Ingrid Kassner for critical reading of the manuscript, and Qiong Tong, Kay Diederichs and Stefanie Fischer for their help with figure preparation. Work in our laboratories was supported by the German Research Foundation (grant GR 1517/2–3) and the Fritz Thyssen Foundation (grant Az. 10.05.1.145).
References (73)
A heat-stable polypeptide component of an ATP -dependent proteolytic system from reticulocytes
Biochem. Biophys. Res. Commun.
(1978)- et al.
A proteasome for all occasions
FEBS Lett.
(2007) Activation of the IκB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain
Cell
(2000)Ubiquitin-dependent proteolytic control of SUMO conjugates
J. Biol. Chem.
(2007)The yeast HEX3-SLX8 heterodimer is a ubiquitin ligase stimulated by substrate sumoylation
J. Biol. Chem.
(2007)Targeting of NEDD8 and its conjugates for proteasomal degradation by NUB1
J. Biol. Chem.
(2001)- et al.
Molecular machinery of autophagosome formation in yeast, Saccharomyces cerevisiae
FEBS Lett.
(2007) UBE1L2, a novel E1 enzyme specific for ubiquitin
J. Biol. Chem.
(2007)E1-L2 activates both ubiquitin and FAT10
Mol. Cell
(2007)Ubiquitin-activating enzyme. Mechanism and role in protein-ubiquitin conjugation
J. Biol. Chem.
(1982)
Conservation in the mechanism of nedd8 activation by the human AppBp1- Uba3 heterodimer
J. Biol. Chem.
Crystal structure of a fragment of mouse ubiquitin-activating enzyme
J. Biol. Chem.
Structural basis for recruitment of Ubc12 by an E2 binding domain in NEDD8's E1
Mol. Cell
Covalent affinity purification of ubiquitin activating enzyme
J. Biol. Chem.
Cloning of ubiquitin activating enzyme from wheat and expression of a functional protein in Escherichia coli
J. Biol. Chem.
Ubiquitin dependence of selective protein degradation demonstrated in the mammalian cell cycle mutant ts85
Cell
Thermolability of ubiquitin-activating enzyme from the mammalian cell cycle mutant ts85
Cell
A Chinese hamster cell cycle mutant arrested at G2 phase has a temperature-sensitive ubiquitin-activating enzyme, E1
J. Biol. Chem.
Transcriptional analysis of the candidate spermatogenesis gene UBE1y and of the closely related Ube1x shows that they are coexpressed in spermatogonia and spermatids but are repressed in pachytene spermatocytes
Dev. Biol.
The structure of the APPBP1-UBA3-NEDD8-ATP complex reveals the basis for selective ubiquitin-like protein activation by an E1
Mol. Cell
The ubiquitin-like protein FAT10 forms covalent conjugates and induces apoptosis
J. Biol. Chem.
Structural analysis of Escherichia coli ThiF
J. Mol. Biol.
FAT10 plays a role in the regulation of chromosomal stability
J. Biol. Chem.
NEDD8 ultimate buster-1L interacts with the ubiquitin-like protein FAT10 and accelerates its degradation
J. Biol. Chem.
The UBA domains of NUB1L are required for binding but not for accelerated degradation of the ubiquitin-like modifier FAT10
J. Biol. Chem.
Structure of ubiquitin refined at 1.8 A resolution
J. Mol. Biol.
Crystal structure of the interferon-induced ubiquitin-like protein ISG15
J. Biol. Chem.
Identification of the enzyme required for activation of the small ubiquitin-like protein SUMO-1
J. Biol. Chem.
Molecular cloning and characterization of human AOS1 and UBA2, components of the sentrin-activating enzyme complex
FEBS Lett.
Identification of the activating and conjugating enzymes of the NEDD8 conjugation pathway
J. Biol. Chem.
A protein conjugation system in yeast with homology to biosynthetic enzyme reaction of prokaryotes
J. Biol. Chem.
The ubiquitin system
Annu. Rev. Biochem.
Ubiquitin Lys63 is involved in ubiquitination of a yeast plasma membrane protein
EMBO J.
Ubiquitin-like protein activation
Oncogene
Ubiquitin-binding domains
Nat. Rev. Mol. Cell Biol.
Modification of proteins by ubiquitin and ubiquitin-like proteins
Annu. Rev. Cell Dev. Biol.
Cited by (94)
The role of abnormal ubiquitination in hepatocellular carcinoma pathology
2024, Cellular SignallingThapsigargin: key to new host-directed coronavirus antivirals?
2022, Trends in Pharmacological SciencesCitation Excerpt :UBA6 and ubiquitin-activating enzyme E1 (UBE1, also called ubiquitin-like modifier-activating enzyme 1, UBA1) are the two main E1 enzymes that redirect proteins to the proteasome [35]. UBA6 can also activate the ubiquitin-like protein (UBL) FAT10 (also called ubiquitin D, UBD) and transfer FAT10 to its substrate proteins for rapid proteasomal destruction [35,36]. FAT10 is upregulated by the proinflammatory mediators interferon γ (IFN-γ), tumor necrosis factor α (TNF-α), or lipopolysaccharide (LPS), and has been found to modify ubiquitin-binding protein p62/sequestosome-1 (p62/SQSTM1), connecting this pathway to autophagy and suggesting a broader role for FAT10 in immune functions [37].
Insights into the evolution of the ISG15 and UBA7 system
2022, GenomicsThe ubiquitin-like modifier FAT10 inhibits retinal PDE6 activity and mediates its proteasomal degradation
2020, Journal of Biological ChemistryUBA6 Inhibition Accelerates Lysosomal TRPML1 Depletion and Exosomal Secretion in Lung Cancer Cells
2024, International Journal of Molecular SciencesIsoform alterations in the ubiquitination machinery impacting gastrointestinal malignancies
2024, Cell Death and Disease