Autophagy—from yeast to humans: Thirty years of molecular autophagy
2024-01-01

The goals and scope of many prestigious journals today encourage authors to submit articles in areas of great biological importance, and autophagy is often and explicitly mentioned here. This has not always been the case. For a long time, the question of how excess or damaged intracellular material is transported to lysosomes/vacuoles for degradation and reuse only interested a few experts studying this macroautophagic (hereafter autophagic) process. Thirty years ago, the pioneering autophagy expert Yoshinori Ohsumi published the identification of the first yeast autophagy genes in FEBS Letters [[1]] and received the Nobel Prize in Physiology or Medicine 2016 for this groundbreaking discovery. The fact that the discovery of autophagy genes has not only opened the door to the molecular understanding of autophagy [[2]] but has also sparked a strong interest in this ancient cellular mechanism in eukaryotes, can be seen in the astonishing number of studies published on autophagy since 1993. A brief search of the first 30 years of autophagy research from 1950 to 1993 yielded below 500 publications, but of the last 30 years from 1993 to 2023, there are over 80 000. This still growing interest in autophagy coupled with the 30th anniversary of the discovery of the first autophagy mutants in yeast prompted us to create this special issue of FEBS Letters. Here, in the 12 review articles, internationally recognized experts in the field of autophagy research describe important aspects in connection with the pioneering work in the field of autophagy and highlight current findings in relation to the molecular and functional understanding of the autophagy process. The first verifiable report of the use of the term autophagy can be found way back in 1859 [[3]]. However, it was only much later, when Christian de Duve first used the term autophagy in 1963 to describe a lysosomal degradation pathway for cell's own material that the foundation for research into the mechanism of autophagy was laid [[4]]. Back then, the study of autophagy was predominantly based on morphological analysis, for which the use of electron microscopes was of unique importance. Also today, morphological analysis of the various autophagic structures is an essential tool of choice to understand the process more in depth. Recent groundbreaking developments toward super-resolution power of both light and electron microscopy, as well as their combined application, have catapulted research into the formation and maturation of autophagosomes enormously forward [[5]]. In this context, Eskelinen [[6]] here highlights new findings in autophagosome biogenesis through the use of cryo-electron tomography in her expert review. Early on, from the 1960s onwards, biochemical modulators were used to study the process of autophagy. It turned out that the formation of autophagosomes requires the production of phosphatidylinositol-3-phosphate (PI3P), is controlled by metabolic hormones, and that amino acids inhibit autophagy [[7-11]]. On this basis, the intracellular targets were identified, TOR and AMPK, which respond to the large number of different signaling pathways and control the initiation of autophagy [[12]]. These principal signaling pathways are conserved, and the review by Patrice Codogno and colleagues [[13]] provides a historical overview of autophagy control in mammalian systems, and Metur and Klionsky [[14]] address nutrient-controlled signaling pathways in the yeast Saccharomyces cerevisiae. Early pioneering work showed that there are also forms of autophagy in which cytoplasmic material is directly transported into the lysosome of mammalian cells or the yeast vacuole without the cargo being initially sequestered in an autophagosome. Since then, microautophagy has described the lysosomal degradation of small portions of cytoplasmic material [[15]], and chaperone-mediated autophagy the selective degradation of certain proteins in the lysosome [[16]]. Here, Sakai and Oku [[17]] discuss the process of microautophagy and present current findings on the control mechanisms of different forms of microautophagy. In addition to the early breakthrough discoveries in autophagy research mentioned above, the principle of selective autophagy with respect to the endoplasmic reticulum and peroxisomes was reported in both yeast and mammalian systems in the late 1970s [[18, 19]]. Since then, many different forms of selective autophagy have been reported [[20, 21]], and in our special issue here, Ryan and Rubinsztein [[22]] address selective autophagy of stress granules in the context of neurodegenerative diseases. Then, in 1993, the molecular era of autophagy research began with the isolation of S. cerevisiae mutants defective in autophagy, followed by the identification of the corresponding yeast ATG (autophagy related) genes [[2, 23, 24]]. The sophisticated molecular mechanisms of autophagosome biogenesis and their fusion with the vacuole with a focus on S. cerevisiae as a model organism are detailed in the graphical review by Shatz and Elazar [[25]], and the review by Kraft and Reggiori [[26]]. The elegant structural and functional relationship of the autophagic machinery is further dissected in the review by Noda [[27]]. The review by Tooze et al. [[28]] pays particular attention to new, profound molecular insights into the specific role of ATG8 in autophagosome biogenesis. This review article demonstrates the molecular detail with which current autophagy research provides important insights into the specific functions of the individual parts of the autophagy machinery. Moreover, a detailed insight into the regulation of the initiation complex for autophagosome biogenesis is provided by describing the metamorphosis of the HORMA domain proteins ATG13 and ATG101 in the review by Nguyen and Faesen [[29]]. With the identification and characterization of ATG genes in mammals, often highly conserved orthologues and paralogues of the yeast ATG genes, the physiological roles of autophagy and its enormous relevance for many human diseases, such as cancer and neurodegeneration, begun to be unraveled [[30-32]]. In fact, the discovery of human BECN1/Beclin 1 in 1999 as a haploinsufficient tumor suppressor [[30]] and essential component of the PI-3 kinase complex that produces PI3P during autophagy initiation has triggered tremendous enthusiasm to study autophagy due to its relevance to human cancer [[33]]. In this context, the human WIPI genes encoding PI3P-binding β-propellers that evolved from the ancestral yeast Atg18 [[34, 35]] have been identified in 2004 to be aberrantly expressed in human cancer and to fulfill important roles in autophagy [[36]]. Their functions as PI3P effectors in autophagy and consequences of human WIPI gene mutations causing rare forms of neurodegeneration, as found initially for WDR45/WIPI4 [[37, 38]], are summarized here by Proikas-Cezanne et al. [[39]]. The special role of autophagy in fighting more common forms of neurodegenerative diseases is highlighted by Ryan and Rubinsztein [[22]], a pioneer in unrevealing the functional connection between autophagy and neurodegeneration [[40]]. In the context of deciphering the role of autophagy in maintaining human health, it is further important to highlight that autophagy has a specific role in innate immunity [[41]], as discussed in the comprehensive review by Colombo and colleagues [[42]]. Particularly in recent years, the causal relationship between defective autophagy and human diseases has begun to be understood in molecular detail. However, despite major advances in understanding the mechanism and importance of autophagy for human health, key questions remain unanswered. How can autophagy be modulated therapeutically to treat various human diseases? Would it be advisable to enhance autophagy in advanced age to prevent neurodegeneration? And at the mechanistic level, how is phagophore closure and autophagosome maturation regulated? We can therefore remain curious to see what the next 30 years of autophagy research will bring. But one thing is for sure. It continues to be an exciting journey. Tassula Proikas-Cezanne is a professor (APL) for molecular biology and cell biology at the University of Tübingen. She identified the human WIPI genes and her interest focusses on the regulation of WIPI β-propellers and their roles in the process of autophagy in the context of cancer and neurodegeneration. Michael Thumm is a professor for biochemistry and molecular cell biology at the University of Göttingen. He identified key yeast ATG genes, and since then, his long-standing research interest lays on the molecular mechanism and the physiological function of macro- and microautophagy in the yeast S. cerevisiae.