The mammalian ULK1 complex and autophagy initiation.

Maria Zachari,Ian G Ganley,Jon D Lane,Viktor I Korolchuk,James T Murray

doi:10.1042/ebc20170021

Maria Zachari, Ian G Ganley + Show 3 more

Open Access

https://doi.org/10.1042/ebc20170021

Copy DOI

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.

Highlights

IntroductionMacroautophagy (hereafter autophagy) is a major catabolic pathway involving the generation of a double-membrane, vesicle-like autophagosome in which cytoplasmic components, be they protein complexes or whole organelles, are sequestered and delivered to lysosomes for degradation (see Figure 1)
Macroautophagy is a major catabolic pathway involving the generation of a double-membrane, vesicle-like autophagosome in which cytoplasmic components, be they protein complexes or whole organelles, are sequestered and delivered to lysosomes for degradation
unc-51-like kinase 1 (ULK1)’s serine/threonine protein kinase activity is required for starvation-induced autophagy

Summary

Introduction

Macroautophagy (hereafter autophagy) is a major catabolic pathway involving the generation of a double-membrane, vesicle-like autophagosome in which cytoplasmic components, be they protein complexes or whole organelles, are sequestered and delivered to lysosomes for degradation (see Figure 1). Autophosphorylation of ULK1 at residues Ser1042 and Thr1046 results in recruitment of KLHL20, the substrate adaptor that allows Cullin-3-mediated ubiquitylation and concomitant degradation of ULK1, as well as ATG13 and components of the VPS34 complex This terminates autophagy and prevents an excessive autophagic response [35]. A recent study suggests that IRGM (immunity-related GTPase family M protein), a small GTPase protein involved in the innate immune response, regulates AMPK activation and concomitantly AMPK-dependent ULK1 activation Apart from this indirect role, it binds to ULK1 and BECLIN-1 in order to mediate their assembly and promote autophagy in response to antimicrobial and inflammatory signalling [38].

Conclusion

Summary