Remove, Reuse, Recycle

OUTLOOK MEDICAL RESEARCH NILS-PETTER EKWALL NILS-PETTER MOLECULAR BIOLOGY Remove, reuse, recycle Waste removal is not usually described as sexy, but the once-neglected field of autophagy — which plays a part in cancer and other diseases — is a hot topic in biomedical research. BY MICHAEL EISENSTEIN Autophagy was once considered to be little Autophagy was discovered in the 1960s, more than a cellular recycling bin — a process based on microscopic observations of selec- hen Ana María Cuervo began by which cells break down unwanted biomol- tive degradation of cellular material within the researching her thesis in autophagy ecules into raw materials. But more recent lysosome (see ‘A history of autophagy’). Over — a cellular recycling mecha- research has revealed that autophagy is, in fact, time, scientists accumulated evidence that this Wnism — little did she know that two decades a nexus for the cellular stress response and a process helped cells to deal with nutrient-poor later she would be working in one of the most failure point for many diseases. In the past conditions, to eliminate excess proteins and dynamic fields of medical research. Randy ten years, researchers have made connections even to remove entire mitochondria — the Schekman, winner of last year’s Nobel Prize between autophagy and the immune response, cell’s metabolic power plants. However, most in Physiology or Medicine, even chose to talk cancer, neurodegeneration and ageing, says functions seemed to fall under the umbrella about autophagy in his opening address to the Daniel Klionsky of the University of Michigan of basic maintenance, and autophagy research 37 laureates and 600 young scientists at this in the United States. “The field just exploded.” remained a niche field. year’s meeting instead of cellular trafficking The turning point that showed autophagy — his prizewinning work. Cuervo is accus- A PROMOTION FROM HOUSEKEEPING was not simply cellular housekeeping came tomed to this rise in interest. “I did my thesis on There are different types of autophagy, but the in the mid-1990s, when a number of proteins autophagy in the early 1990s when autophagy best-understood pathway is known as ‘macro- (now known as Atg proteins) that collectively wasn’t cool,” says Cuervo, who is now co-direc- autophagy’ — a bulk mechanism for gather- mediate the formation and maturation of the tor of the Einstein Institute for Aging Research ing up and degrading proteins, organelles and phagophore were reported. Since then it has at the Albert Einstein College of Medicine in other cellular materials. The process begins become clear that the Atg machinery inter- New York City. “When I finished, everybody with the formation of a double-membrane sects with physiological processes underlying told me to change fields because autophagy was structure known as a phagophore, which elon- an array of disorders, but scientists are still a dead end,” she confesses. Studies have proved gates and engulfs nearby cellular components struggling to figure out the conditions that this prediction to be spectacularly wrong. (see ‘Eating up the cell’). autophagy prevents or promotes. S2 | NATURE | VOL 514 | 16 OCTOBER 2014 © 2014 Macmillan Publishers Limited. All rights reserved MEDICAL RESEARCH OUTLOOK CANCER CONTROVERSY By contrast, some forms of Parkinson’s Autophagy seems to provide a crucial bulwark are associated with disruptions in a paral- EATING UP THE CELL against genetic and biochemical damage — for lel autophagy pathway called chaperone- Autophagy is part of a cell’s normal function, removing proteins, damaged organelles and other example, by eliminating damaged mitochon- mediated autophagy in which specific proteins unwanted material. Failure of the system is dria that would otherwise leak toxic molecules are delivered directly to the lysosome for deg- implicated in a number of conditions and ageing. into the cell. As such, it is perhaps unsurprising radation by means of a protein called LAMP2A that cancer was the first disease to be linked without involvement of the autophagosome. with autophagy. However, current evidence One of the proteins normally removed Lysosome suggests that autophagy can act as both an ena- by this process is α-synuclein, the plaque- Cell bler of and a protector against tumour growth, forming protein associated with Parkinson’s. Components Pre-phagophore creating some debate in the field. Mutant forms of the protein or an excessive (organelles structure and cytoplasm) In 1999, Beth Levine and her colleagues at production of it can gum up the system and to be recycled Columbia University, New York, showed that cause a gradual but steady decline in neuronal RELATED CONDITIONS a protein called beclin-1 suppresses tumour health. “Chaperone-mediated autophagy A double membrane called activity in humans and promotes early forma- cannot remove the molecules at the normal the phagophore starts to grow tion of the phagophore1. The group also found rate, and the protein begins to accumulate,” inside the cell, encasing the components to be recycled. Herpes virus that several cellular pathways that drive tumour says Cuervo. The normal autophagic process Stalls growth inhibit autophagy, either by preventing can compensate to a certain extent. However, formation of activation of beclin-1 or by interfering with as Rubinsztein and others have observed, phagophore in other Atg proteins. Levine is waiting for proof α-synuclein can also exacerbate the condition. brain cells. before declaring that autophagy failure itself drives tumour growth, but she believes it makes CONSTRUCTIVE FEEDBACK Parkinson’s and The double membrane Huntington’s for a compelling hypothesis. “The general view The impact of autophagy goes beyond the encloses cell components, diseases is that autophagy plays a protective role against confines of an individual cell — this process forming a structure called Membrane fails the development of cancer,” she says. is also used to regulate metabolic function the autophagosome. to capture However, some scientists believe that throughout the entire body. Cuervo and her material. autophagy can also help advanced tumours to team recently found2 that the liver helps to thrive by allowing cancerous cells to cope with manage metabolism by using chaperone- Tuberculosis the stress associated with competing for lim- mediated autophagy to selectively destroy the Interferes with autophagosome ited nutrients and oxygen, not to mention the enzymes that convert sugar into energy. This maturation. toxicity caused by radiation or chemotherapy. is crucial, says Cuervo, because otherwise the Autophagy inhibitors could, therefore, render liver becomes a “selfish organ” that uses all Alzheimer’s A lysosome fuses with the disease established cancers more vulnerable to treat- the glucose for itself at the expense of other outer membrane of the ment, says oncologist Ravi Amaravadi at the tissues. Along with her colleague Rajat Singh, autophagosome, forming Autophagosome 3 the autolysosome. fails to fuse with University of Pennsylvania in Philadelphia. she has also found that nutrient-sensing lysosome. “The overarching theme is that autophagy is an functions mediated by autophagy help the adaptive stress response that protects the cancer brain to convey that it is time to eat by switch- Lysosome cell in advanced disease,” he says. ing on appetite signals and switching off those that indicate satiety. KEEPING A CLEAR MIND Elements of the autophagy machinery also But it is not only cancer that is linked to the act as a line of defence against viruses and bac- failure of autophagy — it also seems to play a teria by diverting would-be cell hijackers to Diabetes and key part in neurodegenerative disorders such the lysosome for destruction. Microbiologist obesity as Alzheimer’s, Parkinson’s and Huntington’s Vojo Deretic at the University of New Mexico in Enzymes from the lysosome Abnormal diseases. These conditions are characterized Albuquerque hypothesizes that the autophagy degrade the contents of regulation of the autolysosome. autophagy is a by the formation of dense protein aggregates, machinery may have served as a primordial feature of these which point to some sort of failure in cellular form of immunity in early evolutionary history, conditons. housekeeping, but disruptions vary consider- by helping the body to distinguish between ably between the conditions. molecular signatures that represent foreign For example, neurons in Alzheimer’s patients threats and those that are indicators of ‘self’ exhibit increased numbers of autophagosomes, and should be ignored. the membranes that enclose the cell compo- Many pathogens have evolved strategies that nents before they are broken down, yet they can can sabotage autophagy, which Deretic first no longer fuse effectively with the lysosome. encountered while attempting to understand The degraded molecules, or metabolites, Although the roots of Alzheimer’s pathology how Mycobacterium tuberculosis lives inside are released and are ready to be reused. remain unclear, with toxicity linked to accumu- immune cells. He found4 that the bacteria were lation of two proteins called tau and amyloid-β escaping destruction by selectively attacking a (Aβ), autophagic failure could provide a rea- molecule that would otherwise transport them With so many crucial processes seemingly sonable explanation for either pathway. “At to the lysosome. Likewise, Levine has observed5 converging on a single cellular pathway, the late stages of disease you get what looks

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