The incredible ULKs

Abstract

Macroautophagy (commonly abbreviated as autophagy) is an evolutionary conserved lysosome-directed vesicular trafficking pathway in eukaryotic cells that mediates the lysosomal degradation of intracellular components. The cytoplasmic cargo is initially enclosed by a specific double membrane vesicle, termed the autophagosome. By this means, autophagy either helps to remove damaged organelles, long-lived proteins and protein aggregates, or serves as a recycling mechanism for molecular building blocks. Autophagy was once invented by unicellular organisms to compensate the fluctuating external supply of nutrients. In higher eukaryotes, it is strongly enhanced under various stress conditions, such as nutrient and growth factor deprivation or DNA damage. The serine/threonine kinase Atg1 was the first identified autophagy-related gene (ATG) product in yeast. The corresponding nematode homolog UNC-51, however, has additional neuronal functions. Vertebrate genomes finally encode five closely related kinases, of which UNC-51-like kinase 1 (Ulk1) and Ulk2 are both involved in the regulation of autophagy and further neuron-specific vesicular trafficking processes. This review will mainly focus on the vertebrate Ulk1/2-Atg13-FIP200 protein complex, its function in autophagy initiation, its evolutionary descent from the yeast Atg1-Atg13-Atg17 complex, as well as the additional non-autophagic functions of its components. Since the rapid nutrient- and stress-dependent cellular responses are mainly mediated by serine/threonine phosphorylation, it will summarize our current knowledge about the relevant upstream signaling pathways and the altering phosphorylation status within this complex during autophagy induction.

Drosophila Fip200 is an essential regulator of autophagy that attenuates both growth and aging

“…[32][33][34] On the other hand, Atg1 also has autophagy-independent functions, especially in neurons, where it controls axonal transport, growth and projection. 12 Correspondingly, Atg1 mutation in Drosophila produces strong pleiotropic phenotypes including diminished autophagic activities, cell growth enhancement and defects in axonal transport and projection. [20][21][22][23][24] Drosophila Fip200-null mutants, described in this paper for the first time, also exhibited strong autophagy defects and TORC1-S6k activation, which suggests that Fip200 mediates most of Atg1 function in autophagy and cell growth control.…”

“…A family of protein kinases named Atg1 (in yeast and Drosophila), UNC-51 (in worms) or ULK1/2/3/4 (in mammals) is shown to be an evolutionarily conserved component that is essential for autophagy initiation. 12 Diverse cell growth-stimulating signals such as nutrients and growth factors suppress autophagy through target of rapamycin complex 1 (TORC1)-mediated inhibitory phosphorylation of ULK1. 13 On the other hand, during energetic stress, autophagy is induced through AMP-activated protein kinase (AMPK)-mediated activatory phosphorylation of ULK1.…”

La formation de l’autophagosome

“…Les mitochondries, et plus particulièrement les sites de contact entre RE et mitochondries, participent en premier lieu activement à l'initiation de la biogenèse de l'autophagosome [10] ; cependant, il a également été démontré que l'appareil de Golgi [8,11], la membrane plasmique et les endosomes [12,13], notamment les endosomes de recyclage, qui assurent le transport et la connexion entre les endosomes précoces et la membrane plasmique [14], prennent part à la mise en place des échafaudages moléculaires nécessaires à la formation de l'autophagosome [15] (➜). Enfin, comme précédemment cité, un ballet de protéines spécialisées, essentiellement des protéines ATG, régule finement les étapes liées à la mise en place de l'omégasome et du phagophore, de même que les étapes en amont de ces événements membranaires, lors de la (des) signalisation(s) de stress, notamment via les protéines ULK1/2 ([Unc]-51-like kinase 1/2), ATG13 et FIP200 (FAK family kinaseinteracting protein of 200 kDa) qui dialoguent avec le complexe mTOR1 (mammalian target of rapamycin complex 1) [16] (Figure 2). Les premières protéines ATG (ou assimilées) à être recrutées lors des phases précoces de formation du futur phagophore sont des protéines régulatrices contrôlant l'adressage et les propriétés du complexe PI3kinase de classe III (égale-ment présent à la membrane de l'endosome précoce) composé de la protéine VPS34 et de la protéine accessoire VPS15/P150.…”

Regulation of Autophagy by Protein Phosphorylation

“…There exist at least five Atg1 homologs, designated as Unc-51-like kinases 1-4 (Ulk1-4) and STK36 (reviewed in [14][15][16][17]). Unc-51 (uncoordinated-51) is the single Atg1 homolog in C. elegans [3,15].…”

“…There exist at least five Atg1 homologs, designated as Unc-51-like kinases 1-4 (Ulk1-4) and STK36 (reviewed in [14][15][16][17]). Unc-51 (uncoordinated-51) is the single Atg1 homolog in C. elegans [3,15]. Especially Ulk1 and Ulk2 have been well characterized as the functional homologs of Atg1/Unc-51, and only these two Unc-51-like kinases exclusively exhibit high similarity in both the N-terminal catalytic domain and the rest of the protein, including a central proline/serine-rich (PS) and the C-terminal domain (CTD) [16,17].…”