History of the Selective Autophagy Research: How Did It Begin and Where Does It Stand Today?

Abstract

Autophagy, self-eating, is a pivotal catabolic mechanism that ensures homeostasis and survival of the cell in the face of stressors as different as starvation, infection, or protein misfolding. The importance of the research in this field was recognized by the general public after the Nobel Prize for Physiology or Medicine was awarded in 2016 to Yoshinori Ohsumi for discoveries of the mechanisms of autophagy using yeast as a model organism. One of the seminal findings of Ohsumi was on the role ubiquitin-like proteins (UBLs)-Atg5, Atg12, and Atg8-play in the formation of the double-membrane vesicle autophagosome, which is the functional unit of autophagy. Subsequent work by several groups demonstrated that, like the founding member of the UBL family ubiquitin, these small but versatile protein and lipid modifiers interact with a plethora of proteins, which either directly regulate autophagosome formation, for example, components of the Atg1/ULK1 complex, or are involved in cargo recognition, for example, Atg19 and p62/SQSTM1. By tethering the cargo to the UBLs present on the forming autophagosome, the latter proteins were proposed to effectively act as selective autophagy receptors. The discovery of the selective autophagy receptors brought a breakthrough in the autophagy field, supplying the mechanistic underpinning for the formation of an autophagosome selectively around the cytosolic cargo, that is, a protein aggregate, a mitochondrion, or a cytosolic bacterium. In this historical overview, I highlight key steps that the research into selective autophagy has been taking over the past 20 years. I comment on their significance and discuss current challenges in developing more detailed knowledge of the mechanisms of selective autophagy. I will conclude by introducing the new directions that this dynamic research field is taking into its third decade.

Keywords: Atg8; GABARAP; LC3; SAR; UBL.

Graphical abstract

Fig. 1

Publication dynamics in the field of selective autophagy. Main graph: The numbers of publications per year are shown for the selective autophagy research field; selected discoveries that shaped the field are indicated. Inset graph: Comparison of the publication dynamics in the broader autophagy field versus that of selective autophagy. Note that in the PubMed database, the term “autophagy” was used to derive numbers of publications in the entire autophagy research field, while the combination of the following terms”selective autophagy“ OR “mitophagy” OR “aggrephagy” OR “xenophagy” OR “pexophagy” OR “ribophagy” OR “lipophagy” OR “zymophagy” OR “granulophagy” OR “nucleophagy” OR “glycophagy” OR “lysophagy” OR “ERphagy” OR “reticulophagy” OR “Cvt pathway” OR “ferritinophagy” was used to obtain the number of publications in the field of selective autophagy only. Abbreviations: Atg, autophagy-related; ER, endoplasmic reticulum; LIR, LC3 interacting region; SAR, selective autophagy receptor.

Fig. 2

Key discoveries that have shaped the field of selective autophagy over the past 20 years. Note that not all relevant discoveries could be included due to space limitation. Abbreviations: Atg, autophagy related; Cvt, cytoplasm to vacuole targeting; ER, endoplasmic reticulum; IMM, inner mitochondrial membrane; LIR, LC3 interacting region; SAR, selective autophagy receptor; SLR, sequestosome-1-like receptor; UFIM, UFM1 interacting motif.

Fig. 3

Main selective autophagy processes and their receptors. Main selective autophagy processes and the respective SARs in yeast versus mammalian cells are shown. Insets: Current lists of SLRs in yeast and mammals are provided. Abbreviations: Atg, autophagy related; Cvt, cytoplasm to vacuole targeting; SAR, selective autophagy receptor; SLR, sequestosome-1-like receptor.

Fig. 4

A simplified model of selective autophagosome formation. Based on studies using yeast as a model organism, the following steps of selective autophagosome formation can be discerned: (1) Oligomeric cargo is labeled by SARs. Oligomerization of the SARs (not shown) can further contribute to the cargo/receptor complex formation. (2) SARs recruit the Atg1- and Atg9-binding adaptor Atg11 as well as Atg8, which may or may not be conjugated to PE (not shown) at this step. The SAR:Atg11 and SAR:Atg8 interactions can be regulated by post-translational phosphorylation (not shown). (3) Atg11 and Atg8 recruit the components of the Atg1 kinase complex responsible for the activation of the catalytic cascade that leads to the production of the selective autophagosome in situ (4). In addition, both Atg11 and components of the Atg1 complex interact with the transmembrane protein Atg9 anchored in the Atg9 vesicles, regulating the growth of the lipid membrane. Multiple components of the system, such as Atg11 and the Atg1 complex, are oligomeric (not shown), which further contributes to the formation of the selective autophagosome (4). Abbreviations: Atg, autophagy-related, Cvt, cytoplasm to vacuole targeting; SAR, selective autophagy receptor.