Self and nonself: how autophagy targets mitochondria and bacteria

Abstract

Autophagy is an evolutionarily conserved pathway that transports cytoplasmic components for degradation into lysosomes. Selective autophagy can capture physically large objects, including cell-invading pathogens and damaged or superfluous organelles. Selectivity is achieved by cargo receptors that detect substrate-associated "eat-me" signals. In this Review, we discuss basic principles of selective autophagy and compare the "eat-me" signals and cargo receptors that mediate autophagy of bacteria and bacteria-derived endosymbionts-i.e., mitochondria.

Figure 1. Domain structure and ligands of cargo receptors, E3 ligases and miscellaneous proteins mediating mitophagy and anti-bacterial autophagy

Shared domains and ligands are colour-coded, unique domains and ligands in grey. Panel A modified from (Boyle and Randow, 2013).

Figure 2. PINK1 and Parkin mediate mitochondrial quality control by inducing mitophagy

Insert in upper right: PINK1 is constitutively degraded in healthy mitochondria through import via TIM and TOM translocation complexes and cleavage by PARL in the inner membrane followed by proteosomal degradation. Mitochondrial damage prevents PINK1 import and cleavage, allowing the kinase to accumulate on the outer membrane. Top left to bottom right: When a mitochondrion loses membrane potential or accumulates misfolded proteins, PINK1 accumulates on the outer mitochondrial membrane. The PINK1 kinase recruits Parkin to mitochondria from the cytosol and activates the E3 ligase to ubiquitinate outer mitochondrial membranes. These ubiquitinated proteins act as “eat-me” signals for cargo adaptors that signal autophagosome engulfment of the mitochondrion.

Figure 3. Targeting of intracellular bacteria for lysosomal destruction by xenophagy

Top: Phagosomes mature constitutively and ultimately deliver their bacterial cargo to lysosomes. During LC3-assisted phagocytosis (LAP), conjugation of LC3/GABARAP to the limiting phagosomal membrane promotes phagosome maturation. Bottom: On damaged vacuoles, exposure of otherwise hidden glycans recruits the danger receptor galectin-8, whose accumulation provides an ‘eat-me’ signal for the cargo receptor NDP52, thereby induces autophagy. The ubiquitin-coat deposited by LRSAM1 and Parkin around cytosol-exposed bacteria (which may still be in association with vacuolar membrane remnants) serves as an alternative ‘eat-me’ signal for multiple cargo receptors (NDP52, Optn, p62), thereby inducing autophagy.