autophagy; cancer; phase I trial; translational; treatment
satirical verse; autophagic poetry; mitophagy; phagophore assembly site; imaginary conversation; anthropomorphic organelles
Macroautophagy is a complex process involving dynamic membrane rearrangements in which parts of the cytoplasm are sequestered within double-membrane phagophores. Upon completion, these structures mature into autophagosomes that fuse with the yeast vacuole or mammalian lysosome, leading to degradation of the cargo and release of the resulting macromolecules back into the cytosol. How can the complexities of macroautophagy best be conveyed to an audience that is composed primarily of people who are not experts in this topic, and possibly not even scientists? The literature on learning is vast, and difficult to summarize, but there are certain themes that frequently appear. First, people learn in different ways. Thus, for example, while lectures are effective for conveying information to part of the audience, some will benefit tremendously from alternative methods of presentation. The latter can be visual (taking the form of illustrations, videos, or even physical movement), tactile or audible. Second, a line of research suggests that the engagement of more than one part of the brain (dual channels) improves learning. We decided to explore these concepts focusing on an audible format through a collaborative approach by combining a scientific explanation of macroautophagy with a musical score that was composed specifically to represent this process.
autophagy; degradation; lysosome; music; stress; vacuole
When an autophagosome or an amphisome fuse with a lysosome, the resulting compartment is referred to as an autolysosome. Some people writing papers on the topic of autophagy use the terms “autolysosome” and “autophagolysosome” interchangeably. We contend that these words should be used to denote 2 different compartments, and that it is worthwhile maintaining this distinction—the autophagolysosome has a particular origin in the process of xenophagy that makes it distinct from an autolysosome.
amphisome; lysosome; phagophore; stress; xenophagy
Multiple papers have been published that have identified and/or characterized the cytoprotective function of autophagy, primarily in tumor cells exposed to chemotherapy or radiation. These studies have relied on pharmacological and/or genetic interference with autophagy to establish its protective function, often primarily by demonstrating that cells in which autophagy has been suppressed undergo increased apoptosis. The purpose of this Editor’s Corner is to emphasize that these approaches, while absolutely necessary, are of themselves insufficient to support the conclusion that autophagy is cytoprotective in a given experimental tumor line exposed to a particular agent; complementary studies are required that demonstrate that autophagy inhibition sensitizes the tumor cell to the autophagy-inducing treatment. Otherwise, autophagy may be responsible for the growth arrest and/or cell death that is observed with the drug or radiation treatment alone, and autophagy inhibition may simply be converting one form of growth inhibition/cell death to an alternative pathway that achieves the same end result in terms of sensitivity to the treatment.
cytoprotective autophagy; cell death; chemotherapy; radiation; tumor cell
A glance through Autophagy or any other journal in this field shows that it is very common to block autophagy by RNA interference-based knockdown of ATG mRNAs in mammalian cell lines. Our lab’s experience is that this approach can easily make for failed experiments because good knockdown of even essential autophagy regulators does not necessarily mean you will get good inhibition of autophagy, and, over time, cells can find ways to circumvent the inhibitory effects of the knockdown.
autophagy; shRNA; ATG5; knockdown; RNA interference
In the course of my work as Autophagy editor, I try to gauge the overall patterns of interest in autophagy research. Not surprisingly, the number of papers associated with this topic has increased steadily. However, that trend provides only one glimpse into the way interest in this field has been changing—that the number of people working on autophagy has expanded. Perhaps not surprisingly, the number of different research areas that now include autophagy studies is also increasing. Thus, I decided to carry out an informal, imprecise analysis of the number of different journals (presumably reflecting in part the number of topics) that include papers on autophagy.
autophagy; black hole; gravity; lysosome; stress; vacuole
Molecular biology holds the promise not only of increasing our understanding of basic cell biology, but also of advancing our ability to design targeted therapeutic methods for treating a range of diseases. One example that seems to hold tremendous potential is gene therapy, the use of exogenous DNA to replace or suppress a mutant gene in the patient’s genome, or to boost the activity of a normal gene. A recent report (highlighted in a punctum in this issue of the journal) has brought autophagy into the gene therapy realm.
TFEB; lysosome; macroautophagy; α1-antitrypsin deficiency
Macroautophagy mediates recycling of intracellular material by a multistep pathway, ultimately leading to the fusion of closed double-membrane structures, called autophagosomes, with the lysosome. This event ensures the degradation of the autophagosome content by lysosomal proteases followed by the release of macromolecules by permeases and, thus, it accomplishes the purpose of macroautophagy (hereafter referred to as autophagy). Because fusion of unclosed autophagosomes (i.e., phagophores) with the lysosome would fail to degrade the autophagic cargo, this critical step has to be tightly controlled. Yet, until recently, little was known about the regulation of this event and the factors orchestrating it. A punctum in this issue highlights the recent paper by Noboru Mizushima and his collaborators that answered the question of how premature fusion of phagophores with the lysosome is prevented prior to completion of autophagosome closure.
autophagosome; fusion; glycine zipper; lysosome; SNARE
Autophagy has emerged as a significant innate immune response to pathogens. Typically, autophagosomes deliver their contents to lysosomes for degradation. Some pathogens such as Salmonella enterica serovar Typhimurium succumb to autophagy and are transported to lysosomes for degradation. Yet, many professional pathogens, including Legionella pneumophila and Burkholderia cenocepacia, subvert this pathway exploiting autophagy to their advantage.
autophagosomes; bacteria; lysosome fusion; Anaplasma; Legionella; Burkholderia; Francisella
These days, when we talk about the origin of a protein, or even a pathway, we are typically referring to evolutionary lineages based on nucleotide sequences. For example, is a particular protein’s function conserved? How far back did it first appear? Are there homologs in higher eukaryotes? However, a simpler question (or perhaps I should say, a non-molecular biology question) is when was the process first detected in the paleontological record? Of course I assumed that macroautophagy was ancient, but a new finding (see p. 632 in this issue of the journal) provides an unexpected—and exciting—piece of information for our field. For the first time, scientists have discovered fossil evidence for an actual subcellular pathway—and it looks like it might actually be autophagy (I admit I am biased, but you can decide for yourself).
autophagy; fossil; lysosome; stress; vacuole
To tell the truth, I find it difficult to work when flying, or even when sitting in an airport for an extended period of time. So, typically I take along a book to read. And when I truly cannot concentrate, for example when a flight is considerably delayed, I have even been known to resort to word puzzles. Depending on the type, they do not require much attention (that is, you can pick up right where you left off after you glance at the flight status screen for the twentieth or so time, even though you know nothing has changed), or effort (although you need to use a pen or pencil, not a keyboard), but nonetheless they can keep your mind somewhat occupied. I even rationalize doing them based on the assumption that they are sharpening my observational/pattern-finding skills. One type of word puzzle that is particularly mindless, but for that very reason I still enjoy in the above circumstances, is a word search; you are given a grid with letters and/or numbers, and a list of “hidden” terms, and you circle them within the grid, crossing them off the list as you go along. I do admit that the categories of terms used in the typical word searches can become rather mundane (breeds of dog, types of food, words that are followed by “stone,” words associated with a famous movie star, words from a particular television show, etc.). Therefore, on one of my last seminar trips I decided to generate my own word search, using the category of autophagy.
autophagy; lysosome; stress; vacuole; word search
The current working definition of autophagy is the following: all processes in which intracellular material is degraded within the lysosome/vacuole and where the macromolecular constituents are recycled. There are several ways to classify the different types of autophagy. For example, we can separate autophagy into two primary types, based on the initial site of cargo sequestration. In particular, during microautophagy and chaperone-mediated autophagy, uptake occurs directly at the limiting membrane of the lysosome or vacuole. In contrast, macroautophagy—whether selective or nonselective—and endosomal microautophagy involve sequestration within an autophagosome or an omegasome, or late endosomes/multivesicular bodies, respectively; the key point being that in these types of autophagy the initial sequestration event does not occur at the limiting membrane of the degradative organelle. In any case, the cargo is ultimately delivered into the lysosome or vacuole lumen for subsequent degradation. Thus, I think most autophagy researchers view the degradative organelle as the ultimate destination of the pathway. Indeed, this fits with the general concept that organelles allow reactions to be compartmentalized. With regard to the lysosome or vacuole, this also confers a level of safety by keeping the lytic contents away from the remainder of the cell. If we are willing to slightly modify our definition of autophagy, with a focus on “degradation of a cell’s own components through the lysosomal/vacuolar machinery,” we can include a newly documented process, programmed nuclear destruction (PND).
autophagy; lysosome; meiosis; spore; stress; vacuole
autophagosome; lysosome; phagophore; stress; vacuole
There are various definitions of community. A definition that I found in one of my dictionaries is the following: “A social, religious, occupational, or other group sharing common characteristics or interests and perceived or perceiving itself as distinct in some respect from the larger society within which it exists.” Thus, I think it is fair to say that there is a worldwide autophagy community. That is, there is a group of researchers (our occupation), whose members share an interest in autophagy (our common characteristic), and that group is distinct from the larger society (I do not want to begin describing the many ways this applies). But do we feel like a community, and do we need a community? I suggest that a community is indeed beneficial, and I propose one mechanism for enhancing the development of the autophagy community.
lysosome; methods; people; stress; vacuole
The term autophagic cell death (ACD) initially referred to cell death with greatly enhanced autophagy, but is increasingly used to imply a death-mediating role of autophagy, as shown by a protective effect of autophagy inhibition. In addition, many authors require that autophagic cell death must not involve apoptosis or necrosis. Adopting these new and restrictive criteria, and emphasizing their own failure to protect human osteosarcoma cells by autophagy inhibition, the authors of a recent Editor’s Corner article in this journal argued for the extreme rarity or nonexistence of autophagic cell death. We here maintain that, even with the more stringent recent criteria, autophagic cell death exists in several situations, some of which were ignored by the Editor’s Corner authors. We reject their additional criterion that the autophagy in ACD must be the agent of ultimate cell dismantlement. And we argue that rapidly dividing mammalian cells such as cancer cells are not the most likely situation for finding pure ACD.
apoptosis; autophagy; autophagic cell death; cell death; necrosis
Degradation in the lysosome/vacuole is not the final step of autophagy. In particular, for starvation-induced autophagy it is necessary to release the breakdown products back into the cytosol. However, some researchers ignore this last step and simply refer to the endpoint of autophagy as degradation, or perhaps even cargo delivery. In many cases this is not a serious issue; however, the analysis of autophagy’s role in certain diseases makes clear that this can be a significant error.
autophagy; cholesterol; lipids; lysosome; stress
In the August 2009 issue of Autophagy, I indicated that we were launching a new category of article, Protocols. At that time, I noted that we would ultimately be placing these articles on a new site online. Well, that time has finally arrived (see www.landesbioscience.com/journals/autophagy/protocols/ for links to these papers). Therefore, it seems appropriate for me to briefly distinguish among three types of community-oriented papers, Protocol, Toolbox and Resource.
autophagy; lysosome; methods; stress; vacuole
There is little doubt that humans rely on vision as their primary sensory input. However, various studies indicate that audiovisual combinations of data presentation actually enhance the ability of the learner to comprehend the information. We present an example of a musical-biological interface that provides an audible demonstration of SNARE protein function in the process of macroautophagy.
protein targeting; SNARE protein; stress; vacuole; yeast
Skeletal muscle fibers of collagen VI null (Col6a1−/−) mice show signs of degeneration due to a block in autophagy, leading to the accumulation of damaged mitochondria and excessive apoptosis. Attempts to induce autophagic flux by subjecting these mutant mice to long-term or shorter bursts of physical activity are unsuccessful (see Grumati, et al., pp. 1415–23). In normal mice, the induction of autophagy in the skeletal muscles post-exercise is able to prevent the accumulation of damaged organelles and maintain cellular homeostasis. Thus, these studies provide an important connection between autophagy and exercise physiology.
lysosome; metabolism; physiology; stress; vacuole