REPORT


CUTTING-EDGE RESEARCH


Autophagy regulation: recent research and new technologies


Delegates at a recent EuroSciCon meeting were given examples of how the role of autophagy in health and disease has increased over the past few years. Vignir Helgason reports.


The EuroSciCon meeting on autophagy was held at the O2 Arena in early October. The meeting offered new and more experienced researchers, from academia or industry, the opportunity to discuss the role of this fascinating process, focusing on new technologies and most recent findings. It was evident from the list of presenters, all of whom were experts in the field, that this meeting would cover the most recent advances and live up to the high standard expected by delegates.


WHAT IS AUTOPHAGY? The term ‘autophagy’ derives from the Greek words for self (auto) and eating (phagy) and was first introduced in 1963 by Christian de Duve. Autophagy is an evolutionarily conserved catabolic mechanism that involves degradation of unnecessary, dysfunctional and often potentially harmful cellular components in the lysosomes. Recycling of these components has been shown to ensure survival following starvation or metabolic stress by maintaining cellular energy levels and homeostasis.


During the autophagy process, targeted cytoplasmic material is engulfed into vesicles, termed autophagosomes, which are then fused with lysosomes (which provide pH- sensitive proteases) for degradation of the cargo. The physiological role of autophagy has been studied thoroughly over the past decade or so. In the context of health and disease, autophagy has been shown to be involved in various biological functions such


722 THE BIOMEDICAL SCIENTIST


as development, the immune response by contributing to the removal of pathogens, neurodegeneration and responses to anticancer therapy.


MAMMALIAN AUTOPHAGY AND AUTOPHAGOSOME FORMATION In recent years, the molecular regulators have been identified and at least 36 autophagy-related (ATG) genes characterised. Most of these genes were initially identified in yeasts and several of them have now been shown to have functional orthologues in mammalian cells. Some of these regulators were identified in Dr Sharon Tooze’s laboratory, members of which have also contributed significantly to our understanding of the process of autophagosome formation.


The formation of autophagosomes is a complex process that requires major rearrangements of cellular membranes. It starts with the formation of a cup-shaped structure called the phagophore, leading to the creation of the autophagosome, a double- membrane vesicle that directs the isolated material to the lysosomes – the outer membrane of the autophagosome fuses with the lysosomal membrane to form an


autolysosome, where the cargo, together with the inner membrane, is degraded. The sources for the autophagosomal membranes have been thoroughly investigated and debated over the past few years and various membrane compartments have been identified as sources for autophagosomal membranes; it has been suggested that the endoplasmic reticulum (ER), Golgi apparatus, mitochondria, the plasma membrane and recycling endosomes (RE) may all provide a membrane source for autophagosomes or pre-autophagosomal structures. However, the molecular mechanisms underlying these membrane trafficking steps have yet to be clarified. Results from Dr Tooze’s laboratory identified TBC1D14, a Rab guanosine triphosphatase-activating protein (GAP), as a regulator of autophagosome formation; TBC1D14 is involved in regulation of the recycling endosomal trafficking and mediates its effect at an early stage of autophagosome formation. TBC1D14 co-localises with ULK1 (another autophagy protein characterised in Dr Tooze’s laboratory) and tabulates REs, leading to their impaired function and inhibition of autophagosome formation. The steps leading to autophagosome formation have also been studied through visualisation of ATG9, a key protein regulating autophagosome biogenesis. ATG9 resides in the REs, which contribute to autophagosome formation in a Rab11-dependent manner. The source for the autophagosomal membranes has also been studied in Professor David Rubinsztein’s laboratory. As mentioned


‘Autophagy is a catabolic mechanism that involves degradation of unnecessary, dysfunctional and often potentially harmful cellular components in the lysosomes’


DECEMBER 2013


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