ATG5

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]

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]

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]

• Human ATG5 genome location and ATG5 gene details page in the UCSC Genome Browser.