Table 2.
Types of Selective Autophagy and Possible Roles in Physiology and Disease
| Process (Cargo) | Physiological Function | Possible Pathological Consequences of Defects | References |
|---|---|---|---|
| Proteins | Proteostasis | Aberrant signaling/cellular functions related to effects of increased protein (e.g. p62/SQSTMl inflammatory and pro-tumorigenic signaling; autoinflammatory disorders with defects in TRIM-mediated autophagy of inflammasome components; abnormal iron accumulation and ferroptosis in tissues with defects in ferritin degradation) | (Moscat et al., 2016) (Kimura et al., 2015) (Liu et al., 2016) (Latunde-Dada, 2017) |
| Aggrephagy (Protein aggregates) | Removal of misfolded aggregate-prone proteins labeled by ubiquitin | Enhanced accumulation and detrimental consequences of pathogenic proteins targeted by this mechanism (e.g. β-amyloid, mutant huntingtin, a-synuclein, mutant al-antitrypsin) | (Gatica et al., 2018) (Ueno and Komatsu, 2017) |
| Mitophagy (Mitochondria) | Mitochondrial quality control and homeostasis. Removal of damaged mitochondria, paternal mitochondria during embryogenesis, and mitochondria during erythrocyte differentiation Piecemeal degradation for respiratory chain turnover |
Defective mitophagy may contribute to neurodegenerative diseases, aging, cancer, increased ROS-dependent inflammasome activation and genotoxic stress |
(Rojansky et al., 2016) (Drake et al., 2017) |
| ER-phagy (Endoplasmic reticulum) | Control of ER morphology, turnover, ER luminal proteostasis and recovery from stress | Pathological consequences of defects not defined, but hypothetical role in pathologies associated with abnormal UPR and ER intraluminal proteostasis, including pancreatitis and certain metabolic disorders and aggregopathies. Mutation in ER LC3/GABARAP-binding protein, FAM134B leads to hereditary neuropathy in patients; loss of ER LC3-binding protein CCPG1 leads to injury of exocrine pancreas in mice. Defective ER-phagy in mice (due to AT-1 overexpression) leads to segmental progeria with multiple metabolic and inflammatory phenotypes | (Khaminets et al., 2015) (Grumati et al., 2017) (Smith et al., 2018) (Peng et al., 2018) |
| Ribophagy (Ribosomes) | Required for survival during nutrient starvation, providing source of nucleosides to cell | Not yet known if defects in pathway occur in vivo; if so, would be predicted to disrupt adaptive responses to starvation | (Wyant et al., 2018) |
| Lysophagy (Lysosomes) | Prevents cell destruction and inflammation due to leakage of lyso-somal contents when lysosomal membranes are damaged or ruptured | Defects predicted to be associated with increased cytosol invasion of pathogens, increased lysosomal cell death and inflammation, as well as disruption of lysosomal homeostasis (latter postulated to participate in neurodegeneration); lysosomal damage in autophagy-deficient mice results in acute kidney injury | (Maejima et al., 2013) (Yoshida et al., 2017) (Chauhan et al., 2016a) |
| Nucleophagy (Entire Nucleus) | Nuclear destruction necessary for terminal differentiation of keratinocytes; unknown if required for nuclear removal in red blood cells and lens fiber cells | Perturbations may occur in psoriasis, causing parakeratosis (retention of nuclei in stratum comeum of epidermis) | (Akinduro et al., 2016) |
| Nuclear lamina | Promotes Ras-oncogene-induced senescence | Autophagic degradation of lamin B proposed to be a mechanism of tumor suppression; defects may promote oncogenesis and phenotypes associated with decreased cellular senescence. | (Dou et al., 2015) |
| Micronuclei | Removal of micronuclei generated by mitotic aberration (and cytosolic DNA aggregates that resemble micronuclei) | Defects may contribute to genomic instability associated with autophagy deficiency and pro-inflammatory signaling via cGAS activation; neuroinflammatory autoimmune disorder Aicardi-Goutieres syndrome caused by mutation of DNA repair enzyme RNase H2 resulting in accumulation of micronuclei-like cytosolic DNA aggregates | (Rello-Varona et al., 2012) (Bartsch et al., 2017) |
| Retrotransposon RNA |
Degradation of RNA granules containing retrotransposons may favor genomic stability | Deficiency results in increased retrotransposon insertions into the genome | (Guo et al., 2014) |
| Midbody Rings | Degradation of the midbody, an organelle that contains the remnants of cell division machinery, may regulate cellular fate | Deficiency predicted to alter cellular fate; several mutations affecting midbody proteins cause primary encephalopathies, which is also observed with genetically inherited syndromes associated with defects in autophagic flux | (Kuo et al., 2011) (Mandell et al., 2016) |
| Pexophagy (Peroxisomes) | Perixosomal quality control | Defects may contribute to neurodevelopmental disorders associated with mutations in genes involved in pexophagy, inflammation, aging and age-related diseases, diabetes, cancer and neurodegenerative disorders | (Cipolla and Lodhi, 2017) |
| Lipophagy (Lipid Droplets) | Facilitates transport of lipid droplets to lysosomes for catabolism by lysosomal acid lipase; contributes to lipid homeostasis | Defects are postulated to contribute to pathogenesis of metabolic syndrome, non-alcoholic fatty liver disease and alcoholic fatty liver disease; however, role of defects in lipophagy versus general autophagy pathway remain to be elucidated | (Zechner et al., 2017) (Zhang et al., 2018b) |
| Xenophagy (Intracellular pathogens) | Removal of cytoplasmic bacteria or viruses functions in cell-intrinsic immunity | Mutations in genes required for selective autophagy of pathogens result in enhanced microbial virulence in mouse models of tuberculosis and viral infections. | (Mitchell and Isberg, 2017) (Sumpter et al., 2016) (Franco et al., 2017) |