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Review
. 2011 Jul 27;12(7):226.
doi: 10.1186/gb-2011-12-7-226.

Atg8: an autophagy-related ubiquitin-like protein family

Tomer Shpilka  1 , Hilla Weidberg, Shmuel Pietrokovski, Zvulun Elazar
Affiliations
Review

Atg8: an autophagy-related ubiquitin-like protein family

Tomer Shpilka et al. Genome Biol. .

Abstract

Autophagy-related (Atg) proteins are eukaryotic factors participating in various stages of the autophagic process. Thus far 34 Atgs have been identified in yeast, including the key autophagic protein Atg8. The Atg8 gene family encodes ubiquitin-like proteins that share a similar structure consisting of two amino-terminal α helices and a ubiquitin-like core. Atg8 family members are expressed in various tissues, where they participate in multiple cellular processes, such as intracellular membrane trafficking and autophagy. Their role in autophagy has been intensively studied. Atg8 proteins undergo a unique ubiquitin-like conjugation to phosphatidylethanolamine on the autophagic membrane, a process essential for autophagosome formation. Whereas yeast has a single Atg8 gene, many other eukaryotes contain multiple Atg8 orthologs. Atg8 genes of multicellular animals can be divided, by sequence similarities, into three subfamilies: microtubule-associated protein 1 light chain 3 (MAP1LC3 or LC3), γ-aminobutyric acid receptor-associated protein (GABARAP) and Golgi-associated ATPase enhancer of 16 kDa (GATE-16), which are present in sponges, cnidarians (such as sea anemones, corals and hydras) and bilateral animals. Although genes from all three subfamilies are found in vertebrates, some invertebrate lineages have lost the genes from one or two subfamilies. The amino terminus of Atg8 proteins varies between the subfamilies and has a regulatory role in their various functions. Here we discuss the evolution of Atg8 proteins and summarize the current view of their function in intracellular trafficking and autophagy from a structural perspective.

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Figures

Figure 1
Figure 1
Evolution and sequence features of Atg8 genes. (a) Atg8 genes in fungi, animals and intermediate-branching species. A schematic tree, based on a sequence-derived phylogenetic tree, showing the three animal Atg8 subfamilies and their presence in key lineages. The subfamilies appear only in animals. Branching between animals and fungi are Atg8 proteins from the few known unicellular species that diverged after the emergence of fungi and before the emergence of multicellular animals. Shown here are Atg8 proteins from the choanoflagellate Monosiga brevicollis (Mbe) [6], the ichthyosporean Sphaeroforma arctica (Sar) and the amoeba Capsaspora owczarzaki (Cow) [111]. The scheme is based on a tree calculated from protein multiple alignment of Atg8 proteins from representative species with complete and almost complete genomic data. The alignment included 117 conserved amino acid positions. The tree was calculated using the PhyML program version 2.4.4, with 100 bootstrap replicates, four substitution rate categories, the HKY nucleotide substitution model and program-estimated Ts/Tv ratios, gamma shape parameters and invariant proportions as previously described [112]. The subfamily clusters are supported by bootstrap values ranging from 37/100 to 95/100 and also appeared with significant bootstrap values in other trees similarly calculated with different sets of Atg8 genes. The representative species for this scheme were: human, Danio rerio, Xenopus tropicalis, Branchiostoma floridae, Ciona savignyi, Oikopleura dioica, Strongylocentrotus purpuratus, Aplysia californica, Schistosoma mansoni, Schmidtea mediterranea, Drosophila melanogaster, Caenorhabditis elegans, Capitella teleta, Nematostella vectensis, Trichoplax adhaerens, Amphimedon queenslandica, Monosiga brevicollis, Sphaeroforma arctica, Capsaspora owczarzaki, Saccharomyces cerevisiae, Schizosaccharomyces pombe, Allomyces macrogynus, and Tuber melanosporum. (b) Atg8 subfamily sequence features. Sequence logos [113] show the conservation (overall height) and residue prevalence of multiple alignment positions. The alignment includes the core conserved sequence regions, only excluding short non-conserved distal regions of some sequences. The subfamilies are numbered by the coordinates of the human GATE-16, GABARAP and LC3 proteins. Plus signs indicate similar positions between alignments of the GATE-16 and GABARAP subfamilies and between the GABARAP and LC3 subfamilies. Each of the three families is very well conserved across its entire length (apart from the few amino-terminal residues in LC3). The three families are also very similar to each other in most of their positions. The few positions that are only conserved in each family and different between the subfamilies may account for some of the functional differences between the subfamilies. The alignments and logos were constructed as previously described [112], taking into account sequence redundancy and expected amino acid frequencies. Sequences for the alignments were taken from the CDD [114] and PFAM [115] database entries cd01611 and PF02991, respectively, and sequences similar to ones in these entries, from protein sequences and translated genomic and EST sequences found in public sequence databases.
Figure 2
Figure 2
Crystal structures of the Atg8 family members and ubiquitin. All Atg8s share a similar ubiquitin-like fold with two additional amino-terminal α helices. GATE-16 is shown in blue (Protein Data Bank (PDB): 1EO6), GABARAP in green (PDB: 1KOT), LC3B in red (PDB: 1V49) and ubiquitin in gray (PDB: 1UBI). Helix shape represents an α helix; arrow shape represents a β sheet; arrowhead represents the carboxyl termini of β sheets.
Figure 3
Figure 3
Role of Atg8 proteins in intracellular trafficking processes. (a) The GABARAP subfamily members GABARAP (GB) and GABARAP-L1 (GB1) participate in the transport of plasma membrane proteins, such as the GABA(A), κ-opioid and transferrin receptors, from the Golgi to the plasma membrane (PM). (b) The GABARAP and the GATE-16 subfamilies both participate in transport from the ER to the Golgi and within the Golgi apparatus. GABARAP, together with PX-RICS, participates in N-cadherin/β-catenin transport from the ER to the Golgi. GATE-16 has been implicated in intra-Golgi transport through its interaction with Golgi SNARE protein 28 (GOS-28). Both subfamilies can interact with NSF, suggesting that they participate in regulation of membrane fusion events.
Figure 4
Figure 4
Atg8s in autophagy. (a) The conjugation of Atg8 proteins to phosphatidylethanolamine (PE) mediated by a series of steps involving Atg proteins. Following translation, Atg8 proteins are cleaved by the Atg4 protease at the carboxyl terminus to expose a glycine residue. This glycine is then activated by the E1-like enzyme Atg7 and transferred to the E2-like enzyme Atg3. Finally, the conjugation of Atg8 proteins to PE is mediated by the E3-like complex Atg5-Atg12-Atg16. The association of Atg8 proteins with the autophagic membrane is reversible and is mediated by Atg4. (b) The role of Atg8 proteins in the autophagic process. Atg8 proteins are recruited to the autophagic membrane together with autophagic cargo adaptors. On the autophagic membrane Atg8 proteins are conjugated to PE lipids, enabling them to mediate membrane fusion events leading to autophagosome biogenesis. Different Atg8 proteins recruit distinct adaptors and are therefore responsible for the delivery of specific cargo (protein aggregates, organelles such as mitochondria and pathogens) for lysosomal degradation.
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References

    1. Wood V, Gwilliam R, Rajandream MA, Lyne M, Lyne R, Stewart A, Sgouros J, Peat N, Hayles J, Baker S, Basham D, Bowman S, Brooks K, Brown D, Brown S, Chillingworth T, Churcher C, Collins M, Connor R, Cronin A, Davis P, Feltwell T, Fraser A, Gentles S, Goble A, Hamlin N, Harris D, Hidalgo J, Hodgson G, Holroyd S. et al.The genome sequence of Schizosaccharomyces pombe. Nature. 2002;415:871–880. doi: 10.1038/nature724. - DOI - PubMed
    1. VectorBase: I. scapularis. http://iscapularis.vectorbase.org/
    1. Insights into social insects from the genome of the honeybee Apis mellifera. Nature. 2006;443:931–949. doi: 10.1038/nature05260. - DOI - PMC - PubMed
    1. A Database of Drosophila Genes & Genomes. http://flybase.org/
    1. Srivastava M, Simakov O, Chapman J, Fahey B, Gauthier ME, Mitros T, Richards GS, Conaco C, Dacre M, Hellsten U, Larroux C, Putnam NH, Stanke M, Adamska M, Darling A, Degnan SM, Oakley TH, Plachetzki DC, Zhai Y, Adamski M, Calcino A, Cummins SF, Goodstein DM, Harris C, Jackson DJ, Leys SP, Shu S, Woodcroft BJ, Vervoort M, Kosik KS. et al.The Amphimedon queenslandica genome and the evolution of animal complexity. Nature. 2010;466:720–726. doi: 10.1038/nature09201. - DOI - PMC - PubMed