Selective autophagy

Abstract

While starvation-induced autophagy is thought to randomly degrade cellular components, under certain circumstances autophagy selectively recognizes, sequesters, and degrades specific targets via autophagosomes. This process is called selective autophagy, and it contributes to cellular homeostasis by degrading specific soluble proteins, supramolecular complexes, liquid-liquid phase-separated droplets, abnormal or excess organelles, and pathogenic invasive bacteria. This means that autophagy, like the ubiquitin-proteasome system, strictly regulates diverse cellular functions through its selectivity. In this short review, we focus on the mechanism of "selective" autophagy, which is rapidly being elucidated.

Keywords: ATG8-family proteins; autophagy; liquid-liquid phase separation; selective autophagy; selective autophagy receptors.

FIGURE 1

Autophagosome formation. When the ULK1 protein kinase complex1 is translocated to the ER subdomain, PI3K complex I (3) is recruited and the PI(3)P production increases. WIPI binds to PI(3)P and accumulates with its binding partner, ATG2 (4). ATG2 connects the ER to the isolation membrane/phagophore and transports lipids. ATG9, a membrane protein (2), transiently accumulates in the isolation membrane/phagophore and scrambles phospholipids transported by ATG2 from the ER to the cytoplasmic layer of the isolation membrane/phagophore. VMP1 and TMEM41B are ER membrane proteins that have been shown to be involved in regulating the cytoplasmic side of the ER. ATG12 and ATG5 are covalently bound to each other via a ubiquitin‐like conjugation reaction. The ATG12‐ATG5 conjugate forms a complex with ATG16L and localizes to the isolation membrane/phagophore (5), which determines the location of amide bond formation between ATG8 family proteins and PE. For selective autophagy, receptors that bind to both cargo and ATG proteins ensure selectivity. FIP200, a component of the ULK1 protein kinase complex and ATG9, interacts with these receptors to promote the formation of an isolation membrane/phagophore around the cargo. Interaction of these receptors with ATG8 family‐PE results in the elongation of the isolation membrane/phagophore along the substrate

FIGURE 2

Receptors that facilitate selective autophagy by localizing cargo and binding to ubiquitin, and their interaction with ATG8 family proteins. A, Ubiquitin‐binding (left) and cargo‐localizing (right) receptors. B, Binding of AIM to ATG8. AIM adopts an elongated β‐conformation and forms an intermolecular β‐sheet with β2 of ATG8. In addition, the W/Y/F‐X‐X‐L/I/V side chain of the sequence binds to the W‐site between the N‐terminal helix (α1, α2) and the ubiquitin fold, and the L/I/V side chain binds to the L‐site between β2 and α3 in the ubiquitin fold. AIMs often contain acidic or phosphorylated residues that act to enhance affinity by interacting electrostatically with conserved basic residues in ATG8

FIGURE 3

Schematic of the current understanding of the mechanism of selective autophagy. A, Selective autophagy of the Ape1 complex (Cvt pathway). proApe1 is condensed by liquid‐liquid phase separation (forming the Ape1 complex). ATG19, a receptor protein localized on the surface of the Ape1 complex, recruits ATG11 and sequentially assembles ATG proteins to form an isolation membrane/phagophore. The Ape1 complex is transported to the vacuole with client proteins such as Ams1. B, Selective autophagy of p62 bodies. The binding of p62 with ubiquitinated proteins causes liquid‐liquid phase separation and then condensation (p62 bodies). p62 or the p62‐binding protein NBR1 recruits FIP200, and isolation membranes/phagophores are formed by recruitment of ATG proteins. The p62 bodies are degraded in lysosomes with client proteins such as Keap1