PerspectiveCell Biology

Autophagy's Top Chef

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Science  17 Jun 2011:
Vol. 332, Issue 6036, pp. 1392-1393
DOI: 10.1126/science.1208607

In cells, organelles called lysosomes are responsible for breaking down a wide range of cellular material, such as proteins and other organelles, through a process known as autophagy (1). When nutrients are scarce, autophagy allows a cell to break down its own components and recycle important molecules (2). Autophagy involves about 35 autophagy-related genes (ATGs); these genes generate multiprotein complexes that act sequentially (3), much as kitchen assistants work in sequence to prepare a meal. Most of these autophagy assistants have been identified, but not a master chef. On page 1429 of this issue, Settembre et al. (4) describe how transcription factor EB (TFEB), which is already known to coordinate lysosome formation, functions as the master chef of autophagy when cells are starving.

Cells can move cytosolic materials (the cargo) to the lysosomal compartment in many ways. One that has received more attention in recent years involves the use of double-membrane vesicles (autophagosomes) as carriers. Autophagosomes form when whole cytosolic regions or specific organelles are sequestered by a membrane (phagophore) that wraps around them, and then sequesters and seals the selected cargo from the rest of the cytosol (2). Degradation inside autophagosomes occurs when lysosomes fuse with the autophagosome and infuse it with enzymes that break down the cargo (see the figure).

In recent years, investigators have exquisitely dissected the many autophagy-related proteins (Atgs) that participate in this process. This work has revealed that the sequestering membrane is constructed from lipids and proteins shuttled from different organelle membranes (5). We have a good idea about how the cargo is recognized (6), what moves the autophagosomes around the cell (7), and how they fuse with lysosomes (8, 9). However, researchers have questioned the existence of, or even the need for, a master orchestrator of ATG transcription. Autophagy can occur independently of transcription, and when a cell is starving, it makes sense that autophagy may not need transcriptional activation. Why “spend” resources and energy synthesizing new Atgs when the whole purpose of activating autophagy during starvation is to salvage and recycle amino acids to sustain protein synthesis?

Settembre et al. show that, even under starvation conditions, cells produce new Atgs. Two years ago, this same research group identified a gene network that controls the formation of the lysosome (10). Now, they show that the master regulator of that program, TFEB, is also in charge of the autophagic transcriptional program during cell starvation. They found that TFEB is retained in the cytosol through phosphorylation by extracellular signal–regulated kinase 2 (ERK2), a member of the mitogen-activated protein (MAP) kinase family. During starvation, however, reduced phosphorylation by ERK2 leads to mobilization of TFEB into the cell nucleus, and to the activation of a dual transcriptional program that generates new lysosomes and increases autophagy.

Controlling autophagy.

Phosphorylation of TFEB (upper left) by ERK2 retains it in the cytosolic compartment. Upon starvation, reduced ERK2-dependent phosphorylation of TFEB mobilizes it to the nucleus, where it activates a transcription program that controls the formation of both lysosomes (lower left) and genes involved in different steps in the autophagic process (lower right). The TFEB-mediated increase in number of lysosomes and autophagosomes and their faster fusion enhances autophagic degradation.


Most cells have relatively high amounts of Atgs under normal circumstances. As a result, during the first hours of starvation, a cell should be able to make autophagosomes with whatever Atgs are already in the cytosol. If starvation persists, however, then depletion of Atgs could limit the ability of a cell to generate new autophagosomes. Researchers once believed that, in many cells, this type of autophagy did not last more than 6 to 8 hours into starvation. Recent studies, however, suggest that it can continue for days, with the degradation process shifting from proteins to more energetically favorable cargos, such as intracellular lipids (11), over time.

How are cells sustaining autophagy over these longer periods? Recycling of Atgs is one possibility. Some of the structural components of the autophagosome, for example, are recycled back to the cytosol before they fuse with lysosomes (3, 5). This recycling also applies to the lysosomal compartment itself. During starvation, the vast increase in autophagosome formation often means that all existing lysosomes are engaged in fusing with newly formed autophagosomes. As starvation persists, cells also actively recycle components of the lysosomal membrane out of the hybrid vesicles (autophagolysosomes) (12). But most lysosomal enzymes—which are the ones that get the degradative job done—are not retrieved out of the autophagolysosomes. As a result, new synthesis of lysosomal hydrolases may be necessary to transform recycling vesicles into functional lysosomes. The activation of TFEB during starvation provides a solution for both Atg consumption and the need for new lysosomes.

Other transcriptional regulators increase the expression of Atgs, but often only those Atgs involved in the early steps of autophagosome formation (13, 14). The strength of the TFEB-mediated program is that it affects the whole process; it not only generates more autophagosomes, but also accelerates their delivery to lysosomes and, by increasing the number of available lysosomes, facilitates the rapid degradation of substrates. This aspect of the autophagy process is often overlooked. Forming autophagosomes and secluding the materials from the cytosol is not enough. The ultimate purpose of autophagy is to break down the cargo and recycle essential macromolecules, and this only occurs once the lysosomal hydrolases reach the autophagosome through fusion.

Defective autophagy has been linked to common human diseases such as neurodegenerative conditions (e.g., Alzheimer's disease, Parkinson's disease), metabolic disorders (diabetes, obesity), and aging. The formation of autophagosomes is intact or even enhanced in many of these pathologies; it is the failure to degrade these structures that compromises cellular viability (15). Pharmacological interventions have succeeded in enhancing autophagosome formation by suppressing negative regulators. The main concern about this approach, however, is that it could lead to an “autophagic traffic jam” if the cell does not have enough lysosomes to receive all the cargo. The ability of TFEB to control the formation of both lysosomes and autophagosomes makes it a very attractive target for developing new therapies for those conditions in which enhanced autophagy is desirable.

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