ATG5

Last updated
ATG5
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases ATG5 , APG5, APG5-LIKE, APG5L, ASP, hAPG5, autophagy related 5, SCAR25
External IDs OMIM: 604261 MGI: 1277186 HomoloGene: 3566 GeneCards: ATG5
Orthologs
SpeciesHumanMouse
Entrez

9474

11793

Ensembl

ENSG00000057663

ENSMUSG00000038160

UniProt

Q9H1Y0

Q99J83

RefSeq (mRNA)

NM_001286106
NM_001286107
NM_001286108
NM_001286111
NM_004849

Contents

NM_053069
NM_001314013
NM_001358596

RefSeq (protein)

NP_001273035
NP_001273036
NP_001273037
NP_001273040
NP_004840

NP_001300942
NP_444299
NP_001345525

Location (UCSC) Chr 6: 106.05 – 106.33 Mb Chr 10: 44.14 – 44.24 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Autophagy related 5 (ATG5) is a protein that, in humans, is encoded by the ATG5 gene located on Chromosome 6. It is an E3 ubi autophagic cell death. ATG5 is a key protein involved in the extension of the phagophoric membrane in autophagic vesicles. It is activated by ATG7 and forms a complex with ATG12 and ATG16L1. This complex is necessary for LC3-I (microtubule-associated proteins 1A/1B light chain 3B) conjugation to PE (phosphatidylethanolamine) to form LC3-II (LC3-phosphatidylethanolamine conjugate). ATG5 can also act as a pro-apoptotic molecule targeted to the mitochondria. Under low levels of DNA damage, ATG5 can translocate to the nucleus and interact with survivin.

ATG5 is known to be regulated via various stress induced transcription factors and protein kinases.

Structure

ATG5 comprises three domains: a ubiquitin-like N-terminal domain (UblA), a helix-rich domain (HR) and a ubiquitin-like C-terminal domain (UblB). The three domains are connected by two linker regions (L1 and L2). ATG5 also has an alpha-helix at the N terminus where on Lysine 130 conjugation with ATG12 occurs. [5] Both UblA and UbLB are composed of a five-stranded beta-sheet and two alpha-helices, a feature conserved in most ubiquitin and ubiquitin-like proteins. HR is composed of three long and one short alpha helices, forming a helix-bundle structure. [6]

Regulation

ATG5 is regulated by the p73 from the p53 family of transcription factors. DNA damage induces the p300 acetylase to acetylate p73 with the assistance of c-ABL tyrosine kinase. p73 translocates to the nucleus and acts as a transcription factor for ATG5 as well as other apoptotic and autophagic genes. [7]

Programmed Cell Death Protein 4 (PDCD4) is known to inhibit ATG5 expression via inhibition of protein translation. Two MA3 domains on PDCD4 bind to RNA-helicase EIF4A, preventing translation of ATG5 mRNA. [8]

Many protein kinases can regulate activity of the ATG5 protein. Phosphorylation by various kinases are required in order to achieve its active conformation. Under cell stress conditions, the growth arrest and DNA damage 45 beta (Gadd45ß) protein will interact with MAPK/ERK kinase kinase 4 (MEKK4) to form the Gadd45ß-MEKK4 signaling complex. This complex then activates and selectively targets p38 MAPK to the autophagosome to phosphorylate ATG5 at threonine 75. This leads to the inactivation of ATG5 and inhibition of autophagy. [9]

ATG5 can also be regulated post translationally by microRNA. [10]

Function

Autophagy

The ATG12-ATG5:ATG16L complex is responsible for elongation of the phagophore in the autophagy pathway. ATG12 is first activated by ATG7, proceeded by the conjugation of ATG5 to the complex by ATG10 via a ubiquitination-like enzymatic process. The ATG12-ATG5 then forms a homo-oligomeric complex with ATG16L. [11] With the help of ATG7 and ATG3, the ATG12-ATG5:ATG16L complex conjugates the C terminus of LC3-I to phosphatidylethanolamine in the phospholipid bilayer, allowing LC3 to associate with the membranes of the phagophore, becoming LC3-II. After formation of the autophagosome, the ATG12-ATG5:ATG16L complex dissociates from the autophagosome. [12] [13] [5]

Apoptosis

In instances of spontaneous apoptosis or induction of apoptosis via staurosporine, HL-60, or EOL cells, ATG5 undergoes N-terminal cleavage by Calpain-1 and Calpain-2. The cleaved ATG5 translocates from the cytosol to the mitochondria, where it interacts with Bcl-xL, triggering the release of Cytochrome c and activating caspases leading to the apoptotic pathway. [14] [15] This function is independent of its role in autophagy, as it does not require interaction with ATG12.

Cell Cycle Arrest

In response to DNA damage, ATG5 expression is upregulated, increasing autophagy, preventing caspase activation and apoptosis. ATG5 is also responsible for G2/M arrest and mitotic catastrophe by leading to the phosphorylation of CDK1 and CHEK2, two important regulators of cell cycle arrest. [16] Furthermore, ATG5 is capable of translocating to the nucleus and interacting with survivin to disturb chromosome segregation by antagonistically competing with the ligand Aurora B. [16] [17]

Clinical Significance

As a key regulator of autophagy, any suppression of the ATG5 protein or loss-of-function mutations in the ATG5 gene will negatively affect autophagy. As a result, deficiencies in the ATG5 protein and variations in the gene have been associated with various inflammatory and degenerative diseases as aggregates of ubiquitinated targets are not cleared out via autophagy. Polymorphisms within the Atg5 gene have been associated with Behçet's disease, [18] systemic lupus erythematosus, [19] and lupus nephritis. [20] Mutations in the gene promoter for the Atg5 gene have been associated with sporadic Parkinson's disease [21] and childhood asthma. [22] Downregulation of ATG5 protein and mutations in the Atg5 gene have also been linked with prostate, [23] gastrointestinal [24] and colorectal [25] cancers as ATG5 plays a role in both cell apoptosis and cell cycle arrest. Upregulation of Atg5 on the other hand has been shown to suppress melanoma tumorigenesis through induction of cell senescence. [26] ATG5 also plays a protective role in M. tuberculosis infections by preventing PMN-mediated immunopathology. [27]

An Atg5−/− mutation in mice is known to be embryonic lethal. [28] When the mutation is induced only in mice neurons or hepatocytes, there is an accumulation of ubiquitin-positive inclusion bodies and a decrease in cell function. [29] Overexpression of ATG5 on the other hand has been linked to extend mouse lifespan. [30] In the brain, ATG5 is responsible for astrocyte differentiation through activation of the JAK2-STAT3 pathway via degradation of SOCS2. [31] Furthermore, reduction of ATG5 levels in mice brains leads to a suppression in differentiation and increase in cell proliferation of cortical neural progenitor cells through regulation of β-Catenin. [32]

Related Research Articles

Programmed cell death is the death of a cell as a result of events inside of a cell, such as apoptosis or autophagy. PCD is carried out in a biological process, which usually confers advantage during an organism's lifecycle. For example, the differentiation of fingers and toes in a developing human embryo occurs because cells between the fingers apoptose; the result is that the digits are separate. PCD serves fundamental functions during both plant and animal tissue development.

<span class="mw-page-title-main">Autophagy</span> Cellular catabolic process in which cells digest parts of their own cytoplasm

Autophagy is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent regulated mechanism. It allows the orderly degradation and recycling of cellular components. Although initially characterized as a primordial degradation pathway induced to protect against starvation, it has become increasingly clear that autophagy also plays a major role in the homeostasis of non-starved cells. Defects in autophagy have been linked to various human diseases, including neurodegeneration and cancer, and interest in modulating autophagy as a potential treatment for these diseases has grown rapidly.

<span class="mw-page-title-main">BNIP3</span> Protein-coding gene in the species Homo sapiens

BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 is a protein found in humans that is encoded by the BNIP3 gene.

<span class="mw-page-title-main">BECN1</span> Protein-coding gene in the species Homo sapiens

Beclin-1 is a protein that in humans is encoded by the BECN1 gene. Beclin-1 is a mammalian ortholog of the yeast autophagy-related gene 6 (Atg6) and BEC-1 in the C. elegans nematode. This protein interacts with either BCL-2 or PI3k class III, playing a critical role in the regulation of both autophagy and cell death.

<span class="mw-page-title-main">MAP1LC3B</span> Protein-coding gene in the species Homo sapiens

Microtubule-associated proteins 1A/1B light chain 3B is a protein that in humans is encoded by the MAP1LC3B gene. LC3 is a central protein in the autophagy pathway where it functions in autophagy substrate selection and autophagosome biogenesis. LC3 is the most widely used marker of autophagosomes.

<span class="mw-page-title-main">ATG4B</span> Protein-coding gene in the species Homo sapiens

Cysteine protease ATG4B is an enzyme that in humans is encoded by the ATG4B gene.

<span class="mw-page-title-main">ATG10</span> Protein-coding gene in the species Homo sapiens

Autophagy-related protein 10 is a protein that in humans is encoded by the ATG10 gene.

<span class="mw-page-title-main">ATG16L1</span> Protein-coding gene in the species Homo sapiens

Autophagy related 16 like 1 is a protein that in humans is encoded by the ATG16L1 gene. This protein is characterized as a subunit of the autophagy-related ATG12-ATG5/ATG16 complex and is essentially important for the LC3 (ATG8) lipidation and autophagosome formation. This complex localizes to the membrane and is released just before or after autophagosome completion.

<span class="mw-page-title-main">ATG12</span> Protein-coding gene in the species Homo sapiens

Autophagy related 12 is a protein that in humans is encoded by the ATG12 gene.

<span class="mw-page-title-main">ATG9A</span> Protein-coding gene in the species Homo sapiens

Autophagy-related protein 9A is a protein that in humans is encoded by the ATG9A gene.

<span class="mw-page-title-main">ATG7</span> Protein-coding gene in the species Homo sapiens

Autophagy related 7 is a protein in humans encoded by ATG7 gene. Related to GSA7; APG7L; APG7-LIKE.

<span class="mw-page-title-main">ATG4A</span> Protein-coding gene in humans

Cysteine protease ATG4A is an enzyme that in humans is encoded by the ATG4A gene.

<span class="mw-page-title-main">ATG8</span>

Autophagy-related protein 8 (Atg8) is a ubiquitin-like protein required for the formation of autophagosomal membranes. The transient conjugation of Atg8 to the autophagosomal membrane through a ubiquitin-like conjugation system is essential for autophagy in eukaryotes. Even though there are homologues in animals, this article mainly focuses on its role in lower eukaryotes such as Saccharomyces cerevisiae.

AuTophaGy related 1 (Atg1) is a 101.7kDa serine/threonine kinase in S.cerevisiae, encoded by the gene ATG1. It is essential for the initial building of the autophagosome and Cvt vesicles. In a non-kinase role it is - through complex formation with Atg13 and Atg17 - directly controlled by the TOR kinase, a sensor for nutrient availability.

An autophagosome is a spherical structure with double layer membranes. It is the key structure in macroautophagy, the intracellular degradation system for cytoplasmic contents. After formation, autophagosomes deliver cytoplasmic components to the lysosomes. The outer membrane of an autophagosome fuses with a lysosome to form an autolysosome. The lysosome's hydrolases degrade the autophagosome-delivered contents and its inner membrane.

In molecular biology, autophagy related 3 (Atg3) is the E2 enzyme for the LC3 lipidation process. It is essential for autophagy. The super protein complex, the Atg16L complex, consists of multiple Atg12-Atg5 conjugates. Atg16L has an E3-like role in the LC3 lipidation reaction. The activated intermediate, LC3-Atg3 (E2), is recruited to the site where the lipidation takes place.

<span class="mw-page-title-main">Yoshinori Ohsumi</span> Japanese cell biologist

Yoshinori Ohsumi is a Japanese cell biologist specializing in autophagy, the process that cells use to destroy and recycle cellular components. Ohsumi is a professor at Tokyo Institute of Technology's Institute of Innovative Research. He received the Kyoto Prize for Basic Sciences in 2012, the 2016 Nobel Prize in Physiology or Medicine, and the 2017 Breakthrough Prize in Life Sciences for his discoveries of mechanisms for autophagy.

Microautophagy is one of the three common forms of autophagic pathway, but unlike macroautophagy and chaperone-mediated autophagy, it is mediated—in mammals by lysosomal action or in plants and fungi by vacuolar action—by direct engulfment of the cytoplasmic cargo. Cytoplasmic material is trapped in the lysosome/vacuole by a random process of membrane invagination.

<span class="mw-page-title-main">Ubiquitin-like protein</span> Family of small proteins

Ubiquitin-like proteins (UBLs) are a family of small proteins involved in post-translational modification of other proteins in a cell, usually with a regulatory function. The UBL protein family derives its name from the first member of the class to be discovered, ubiquitin (Ub), best known for its role in regulating protein degradation through covalent modification of other proteins. Following the discovery of ubiquitin, many additional evolutionarily related members of the group were described, involving parallel regulatory processes and similar chemistry. UBLs are involved in a widely varying array of cellular functions including autophagy, protein trafficking, inflammation and immune responses, transcription, DNA repair, RNA splicing, and cellular differentiation.

<span class="mw-page-title-main">Rubicon (protein)</span> Human protein involved in autophagy regulation

Rubicon is a protein that in humans is encoded by the RUBCN gene. Rubicon is one of the few known negative regulators of autophagy, a cellular process that degrades unnecessary or damaged cellular components. Rubicon is recruited to its sites of action through interaction with the small GTPase Rab7, and impairs the autophagosome-lysosome fusion step of autophagy through inhibition of PI3KC3-C2.

References

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  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000038160 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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