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The mechanisms and roles of selective autophagy in mammals

Abstract

Autophagy is a process that targets various intracellular elements for degradation. Autophagy can be non-selective — associated with the indiscriminate engulfment of cytosolic components — occurring in response to nutrient starvation and is commonly referred to as bulk autophagy. By contrast, selective autophagy degrades specific targets, such as damaged organelles (mitophagy, lysophagy, ER-phagy, ribophagy), aggregated proteins (aggrephagy) or invading bacteria (xenophagy), thereby being importantly involved in cellular quality control. Hence, not surprisingly, aberrant selective autophagy has been associated with various human pathologies, prominently including neurodegeneration and infection. In recent years, considerable progress has been made in understanding mechanisms governing selective cargo engulfment in mammals, including the identification of ubiquitin-dependent selective autophagy receptors such as p62, NBR1, OPTN and NDP52, which can bind cargo and ubiquitin simultaneously to initiate pathways leading to autophagy initiation and membrane recruitment. This progress opens the prospects for enhancing selective autophagy pathways to boost cellular quality control capabilities and alleviate pathology.

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Fig. 1: Comparison of non-selective autophagy and selective autophagy.
Fig. 2: Receptor protein initiates de novo on damaged mitochondria.
Fig. 3: Mitophagy in health and disease.
Fig. 4: Schematic of lysophagy.
Fig. 5: Receptor recruitment during aggrephagy and xenophagy.

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Acknowledgements

This work was supported by the Intramural Program of the National Institute of Neurological Disorders and Stroke.

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Authors and Affiliations

Authors

Contributions

M.H., T.K. and T.Y. wrote and edited the sections on introduction, lysophagy and xenophagy, and created the figures and a table associated with these sections. J.N.S.V. and R.J.Y. wrote and edited the sections on mitophagy, aggrephagy, autophagy of other cellular structures, therapeutic opportunities, and conclusions and perspectives, and created the figures associated with these sections.

Corresponding authors

Correspondence to Maho Hamasaki, Richard J. Youle or Tamotsu Yoshimori.

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The authors declare no competing interests.

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Nature Reviews Molecular Cell Biology thanks Zvulun Elazar, Hong Zhang and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

LC3/GABARAP proteins

Mammalian paralogs of Atg8 protein. There are over six paralogs of Atg8 in mammals. The paralogs are activated by the processing of the C-terminal residue of LC3 paralogs, exposing G residue that is modified with phosphatidylethanolamine. LC3-phosphatidylethanolamine stably binds to autophagosome and facilitates autophagosome formation and maturation.

TOM and TIM complex

A mitochondrial protein complexe that facilitates the translocation of cytosolic proteins containing a mitochondrial-targeting sequence into the mitochondria.

p97

A protein, member of the AAA-ATPase, also known as valosin-containing protein (VCP) or cdc48.

Reticulocyte

The immature form of red blood cells (erythrocytes) still containing RNA. It is generated from progenitor cells via erythropoiesis, a process accompanied by enucleation in mammals.

ATG9A

A transmembrane protein with a phospholipid scramblase activity that plays a key role in the initiation of autophagy through the delivery of membranes to growing autophagosomes.

ULK1 complex

A protein kinase complex consists of ULK1 kinase, ATG13, ATG101 and FIP200. It promotes the early step of autophagy by facilitating the formation of an isolation membrane.

Mitochondrial antiviral signalling protein

(MAVS). A protein localized on the outer membrane of the mitochondria and activated by viral RNA, leading to increased levels of pro-inflammatory cytokines.

VDAC1

A protein forming a voltage-dependent ion channel on the outer mitochondrial membrane. VDACs are responsible for the transport of nucleotides and metabolites from the cytosol into the mitochondria.

Damage-associated molecular patterns

(DAMPs). Various molecules released during cell death via infection or damage. For instance, mitochondrial DNA released by apoptotic cells act as a DAMP and are recognized by Toll-like receptor 9 expressed by other cells, leading to inflammatory responses.

Amyloid-β

A large transmembrane protein that accumulates in the brain of patients with Alzheimer disease forming amyloid plaques — suggested causative agents of neurodegeneration in Alzheimer disease.

LLOMe

A dipeptide that is activated by lysosome enzyme like cathepsin and ruptures lysosomal membrane.

Galectins

Proteins termed S-type lectins, which bind β-galactoside carbohydrates. They bind to glycoproteins on the inner membrane of endosomes; therefore, endosomal membrane rupture causes the accumulation of galectins, acting as a danger signal provoking selective autophagy.

E3 ubiquitin ligases

Enzymes that selectively modify proteins by covalently attaching ubiquitin.

Beclin 1

The mammalian homologue of yeast Atg6, a component of class III phosphoinositide 3-kinase (PI3K) complex. The BECN1 gene, encoding beclin 1, is located at a locus closed to the BRCA1 tumour suppressor gene and is therefore often deleted together with BRCA1 in breast cancer.

ESCRT-III complex

Long filamentous complex promoting membrane remodelling, nucleation and scission to facilitate endocytosis or generation of multivesicular bodies together with other ESCRT complexes.

Endo-lysosomal damage response

(ELDR). Cellular response triggered by lysosomal damage. ELDR complex contains ubiquitin-directed AAA-ATPase p97, deubiquitinating enzyme YOD1, and cofactors UBXD1 and PLAA.

Multisystem proteinopathy

Defined as a combination of multiple degenerative disorders, such as amyotrophic lateral sclerosis (ALS) and inclusion body myopathy, characterized by the presence of protein aggregates in various organs, including muscle, bone and the central nervous system.

E2 ubiquitin-conjugating enzyme

Enzyme that transfers ubiquitin from ubiquitin-activation enzyme E1 to a target protein through the support of E3.

α-Synuclein

Neuronal protein that regulates synaptic vesicle trafficking and neurotransmitter release. Aggregates of α-synuclein establish insoluble fibrils, which are found in patients with Parkinson disease.

Tau

Protein that functions to stabilize microtubules in axons. When hyperphosphorylated, it forms insoluble aggregates, causative of neurodegenerative diseases such as Alzheimer disease and Parkinson disease.

Huntingtin

Protein involves in axonal transport. Mutants that show expansion of poly-glutamine repeats are causative of Huntington disease.

Cytochrome c

Haeme protein attached to the inner membrane of a mitochondrion. In response to an apoptotic signal, it is released into the cytoplasm and activates caspase 9.

Chaperone-mediated autophagy

A mode of autophagy that utilizes cytosolic HSC70 protein, which binds to targets and the lysosomal membrane protein LAMP2A. It is distinguished from macroautophagy, which is often referred to as just autophagy. Chaperone-mediated autophagy facilitates protein degradation via direct incorporation of proteins without the formation of the autophagosome.

TDP43

An RNA-binding protein that is mutated in ALS. Furthermore, the aggregation of this protein is the neuropathological hallmark of ALS and frontotemporal dementia.

FUS

A protein that functions as an RNA-binding protein. Mutations in FUS lead to early onset ALS.

AMPK

A kinase activated upon stresses that reduce cellular ATP levels to promote a line of pathways that protect cells from the stresses. AMPK and mTOR cooperatively regulate autophagy.

Cytosolic-to-vacuole targeting pathway

A pathway responsible for delivering some cytosolic proteins into vacuoles in yeast. Sharing certain components required for macroautophagy, cytosolic-to-vacuole targeting is considered one form of selective autophagy.

Proteolysis-targeting chimaeras

Heterobifunctional molecules that target E3 ligase complexes to specific substrates to induce the ubiquitylation and subsequent proteasomal degradation of the target.

Lipopolysaccharide

A major component of outer membranes of Gram-negative bacteria. It consists of lipid A, oligosaccharide and the O-antigen. The structure of lipid A and oligosaccharide is shared among many bacteria but that of O-antigen is variable.

NEMO

A protein that is involved in the kinase complex, which facilitates activation of NF-κB. It phosphorylates IκB, invoking nuclear translocation of NF-κB.

mTOR

A protein kinase that senses cellular metabolism, such as nutrients, energy and hormone levels, or exogenous stresses, thereby regulating a variety of cellular actions such as protein synthesis, proliferation, endocytosis and autophagy. mTOR binds to other subunits to form complexes called mTORC1 and mTORC2.

Foam cells

Macrophages containing cholesterol and observed during arteriosclerotic vascular disease.

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Vargas, J.N.S., Hamasaki, M., Kawabata, T. et al. The mechanisms and roles of selective autophagy in mammals. Nat Rev Mol Cell Biol (2022). https://doi.org/10.1038/s41580-022-00542-2

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