Autophagy genes in biology and disease

Abstract

Macroautophagy and microautophagy are highly conserved eukaryotic cellular processes that degrade cytoplasmic material in lysosomes. Both pathways involve characteristic membrane dynamics regulated by autophagy-related proteins and other molecules, some of which are shared between the two pathways. Over the past few years, the application of new technologies, such as cryo-electron microscopy, coevolution-based structural prediction and in vitro reconstitution, has revealed the functions of individual autophagy gene products, especially in autophagy induction, membrane reorganization and cargo recognition. Concomitantly, mutations in autophagy genes have been linked to human disorders, particularly neurodegenerative diseases, emphasizing the potential pathogenic implications of autophagy defects. Accumulating genome data have also illuminated the evolution of autophagy genes within eukaryotes as well as their transition from possible ancestral elements in prokaryotes.

Crosstalk between Autophagy and RLR Signaling

“…Autophagy is a self-digestion process that recycles nutrients and regenerates energy through lysosomal degradation of unwanted intracellular components, such as damaged organelles and aggregated/unfolded proteins [ 127 , 128 , 129 ]. Proper and precise control of autophagy primarily maintains cellular homeostasis, whereas dysregulation of autophagy has been widely shown to be associated with human diseases [ 129 , 130 , 131 ].…”

“…Autophagy is a self-digestion process that recycles nutrients and regenerates energy through lysosomal degradation of unwanted intracellular components, such as damaged organelles and aggregated/unfolded proteins [ 127 , 128 , 129 ]. Proper and precise control of autophagy primarily maintains cellular homeostasis, whereas dysregulation of autophagy has been widely shown to be associated with human diseases [ 129 , 130 , 131 ]. Three types of autophagy have been identified in eukaryotes, including microautophagy, macroautophagy, and chaperone-mediated autophagy (CMA); all three kinds of autophagy involve lysosomal degradation ( Figure 3 ) [ 129 , 132 , 133 , 134 ].…”

“…Proper and precise control of autophagy primarily maintains cellular homeostasis, whereas dysregulation of autophagy has been widely shown to be associated with human diseases [ 129 , 130 , 131 ]. Three types of autophagy have been identified in eukaryotes, including microautophagy, macroautophagy, and chaperone-mediated autophagy (CMA); all three kinds of autophagy involve lysosomal degradation ( Figure 3 ) [ 129 , 132 , 133 , 134 ]. Microautophagy involves the protrusion and/or invagination of the lysosomal membrane to sequester the components of the cytosol, including organelles, and deliver them to the lysosomal lumen for degradation ( Figure 3 A) [ 135 , 136 , 137 , 138 ].…”

“…After recognition by heat shock cognate 70 kDa protein (HSC70), which specifically binds to lysosomal membrane protein 2A (LAMP2A) on the lysosomal membrane, CMA cargoes are then transported into the lumen of lysosomes and degraded by lysosomal proteases ( Figure 3 B) [ 139 , 140 , 141 ]. Macroautophagy, the most common form of autophagy, is a stepwise vacuole biogenesis process involving the formation of double-membranous autophagosomes that sequester cytoplasmic portions and ultimately deliver them to lysosomes for decomposition ( Figure 3 C) [ 129 , 134 , 142 , 143 ]. The completion of autophagy relies on the coordinated regulation of functional autophagy-related genes (ATGs) and the successful rearrangement of intracellular membranes, which is initiated by the nucleation of the isolation membrane (IM)/phagophore [ 129 , 142 , 143 , 144 , 145 ].…”

AlphaFold-multimer predicts ATG8 protein binding motifs crucial for autophagy research

“…Autophagy is a multistep process where a double membrane structure is induced, expands, and encapsulates the cargo to be degraded in a closed vesicle, called the autophagosome, which subsequently fuses with lysosomes that digest the cargo. More than 40 conserved autophagy-related (ATG) proteins are involved in this process [ 4 ]. Among these is the ATG8 family of ubiquitin-like modifiers represented by three LC3- and three GABARAP family proteins in humans.…”