The mammalian ULK1 complex and autophagy initiation

Abstract

Autophagy is a vital lysosomal degradation pathway that serves as a quality control mechanism. It rids the cell of damaged, toxic or excess cellular components, which if left to persist could be detrimental to the cell. It also serves as a recycling pathway to maintain protein synthesis under starvation conditions. A key initial event in autophagy is formation of the autophagosome, a unique double-membrane organelle that engulfs the cytosolic cargo destined for degradation. This step is mediated by the serine/threonine protein kinase ULK1 (unc-51-like kinase 1), which functions in a complex with at least three protein partners: FIP200 (focal adhesion kinase family interacting protein of 200 kDa), ATG (autophagy-related protein) 13 (ATG13), and ATG101. In this artcile, we focus on the regulation of the ULK1 complex during autophagy initiation. The complex pattern of upstream pathways that converge on ULK1 suggests that this complex acts as a node, converting multiple signals into autophagosome formation. Here, we review our current understanding of this regulation and in turn discuss what happens downstream, once the ULK1 complex becomes activated.

ER‐phagy: shaping up and destressing the endoplasmic reticulum

“…The ULK complex is an early‐acting assembly, comprising the scaffolding ATG proteins FIP200 (FAK‐interacting Protein 200 kDa, alias RB1CC1), ATG13, ATG101 and the serine–threonine protein kinases ULK1/2 (Unc51‐like Kinases 1/2) . The enzymatic activities of ULK1/2 promote autophagy and are key signal integrators; phosphorylations of ULK1 by mTORC1 (Mammalian Target of Rapamycin Complex 1) and AMPK (Adenosine Monophosphate‐activated Kinase) inhibit and activate kinase activity, respectively . Upon ULK1/2 activation, the ULK and VPS34 complexes (discussed below) recruit to nascent phagophores, which are generated via deformation, budding and fusion of mixed membrane sources, including endosomes, plasma membrane and the ER .…”

MicroRNAs play an essential role in autophagy regulation in various disease phenotypes

“…Following cellular stress, MTORC1 is inactivated, resulting in the release of the ULK1 complex, its dephosphorylation, and subsequent activation of ULK1 kinase activity. ULK1 then phosphorylates itself and its partners, FIP200 and ATG13, leading to the activation of autophagy by the formation of the ULK‐ATG13‐ATG101‐FIP200 complex . (B): Along with the phosphoinositide 3‐kinase regulatory subunit 4, ATG14, and the scaffold protein Bcl2‐interacting protein 1, phosphatidylinositol 3‐kinase catalytic subunit type 3 forms the class III PI3K complex, which generates a membrane domain enriched in PtsIns3P and creates PI3P (phosphatidylinositol‐3‐phosphate) at the site of nucleation of the phagophore which leads to the binding of PI3P binding proteins, and the subsequent recruitment of proteins involved in “the ubiquitin‐like protein conjugation systems” to the isolation membrane .…”

Neuroprotective effects of curcumin through autophagy modulation

“…These conditions are considered to be the metabolic basis for autophagy activation. Currently, TSC2 is the central station in which access to environmental nutrients or stresses is integrated …”