Abstract
Autophagy plays a critical role in cell metabolism by degrading and recycling internal components when challenged with limited nutrients. This fundamental and conserved mechanism is based on a membrane trafficking pathway in which nascent autophagosomes engulf cytoplasmic cargo to form vesicles that transport their content to the lysosome for degradation. Based on this simple scheme, autophagy modulates cellular metabolism and cytoplasmic quality control to influence an unexpectedly wide range of normal mammalian physiology and pathophysiology. In this review, we summarise recent advancements in three broad areas of autophagy regulation. We discuss current models on how autophagosomes are initiated from endogenous membranes. We detail how the uncoordinated 51-like kinase (ULK) complex becomes activated downstream of mechanistic target of rapamycin complex 1 (MTORC1). Finally, we summarise the upstream signalling mechanisms that can sense amino acid availability leading to activation of MTORC1.
Highlights
All cells are challenged to adapt their metabolic pathways in response to nutritional levels and the resulting states of homeostasis go on to direct downstream decisions on growth, arrest or death.Macroautophagy, hereafter referred to as autophagy, is the intracellular recycling process that supports survival during times of energy stress and nutrient starvation
The model with ATG14L–Beclin 1–VPS34 complexes on endoplasmic reticulum (ER)–mitochondria contact sites may reflect the central pathway for isolation membranes (IM) initiation
Thickness of connectors corresponds to numbers of experimental entries entries supporting interaction
Summary
All cells are challenged to adapt their metabolic pathways in response to nutritional levels and the resulting states of homeostasis go on to direct downstream decisions on growth, arrest or death. Cellular membranes elongate and sequester portions of the cytoplasm to capture a range of targets including proteins, organelles or foreign matter This cargo capture event can be non-specific or directed by a family of adaptor proteins that recognise components labelled for degradation by ubiquitination. The ULK1/2 complex drives initiation of autophagosome formation, leading to increased levels of autophagy. Progress in mammalian autophagy has been essentially founded on studies of the homologous pathways in yeast and other model systems. From these concerted experiments, the field has defined how core features of the regulatory network are conserved while additional layers of complexity have joined during the evolution to higher organisms. We shift towards signalling mechanisms further upstream and discuss the emerging network of sensor pathways that link amino acid availability to the activation of MTORC1
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
