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The emerging mechanisms and functions of microautophagy

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Abstract

‘Autophagy’ refers to an evolutionarily conserved process through which cellular contents, such as damaged organelles and protein aggregates, are delivered to lysosomes for degradation. Different forms of autophagy have been described on the basis of the nature of the cargoes and the means used to deliver them to lysosomes. At present, the prevailing categories of autophagy in mammalian cells are macroautophagy, microautophagy and chaperone-mediated autophagy. The molecular mechanisms and biological functions of macroautophagy and chaperone-mediated autophagy have been extensively studied, but microautophagy has received much less attention. In recent years, there has been a growth in research on microautophagy, first in yeast and then in mammalian cells. Here we review this form of autophagy, focusing on selective forms of microautophagy. We also discuss the upstream regulatory mechanisms, the crosstalk between macroautophagy and microautophagy, and the functional implications of microautophagy in diseases such as cancer and neurodegenerative disorders in humans. Future research into microautophagy will provide opportunities to develop novel interventional strategies for autophagy- and lysosome-related diseases.

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Fig. 1: Macroautophagy, chaperone-mediated autophagy and microautophagy in mammals.
Fig. 2: Selective microautophagy pathways in mammals.
Fig. 3: Molecular mechanisms of micromitophagy in mammals.
Fig. 4: Degradation of cytosolic individual proteins via CMA and microautophagy in mammals.

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Acknowledgements

The authors apologize to colleagues whose work could not be cited owing to space limitations. This work was supported by the following grants: NMRC/CIRG/1490/2018 from the Singapore National Medical Research Council, MOE2018-T2-1-060 from the Singapore Ministry of Education, SRG2020-00002-FHS CPG2020-00029-FHS and CPG2021-00004-FHS from the University of Macau and FDCT0078/2020/A2 and 0031/2021/A1 from the Macau Science and Technology Development Fund to H.M.S., NIH grant GM131919 to D.J.K. and grant number 82071441 from the National Natural Science Foundation of China to L.M.W.

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Authors and Affiliations

  1. School of Biomedical Sciences, Hunan University, Changsha, China

    Liming Wang

  2. Life Sciences Institute and Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI, USA

    Daniel J. Klionsky

  3. Faculty of Health Sciences, Ministry of Education Frontiers Science Center for Precision Oncology, University of Macau, Macau, China

    Han-Ming Shen

  4. Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Han-Ming Shen

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  1. Liming Wang
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The authors contributed equally to all aspects of the article.

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Correspondence to Daniel J. Klionsky or Han-Ming Shen.

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Glossary

Multivesicular body

(MVB). A late endosome formed by invagination of the limiting membrane. On the one hand, MVBs can fuse with an autophagosome to form an amphisome in macroautophagy; on the other hand, in microautophagy, MVBs contain hydrolytic enzymes that function similarly to lysosomes or fuse with lysosomes to degrade autophagic cargoes.

Soluble N-ethylmaleimide-sensitive factor attachment protein receptor

(SNARE). A complex consisting of the SNARE proteins, including Qa, Qb, Qc and R fusion proteins. SNARE complex assembly, through a hetero-oligomeric or four-helix bundle, is responsible for the fusion of different membranes.

ESCRTs

The core ESCRTs machinery consists of five distinct protein complexes — ESCRT-0, ESCRT-I, ESCRT-II, ESCRT-III and vacuolar protein sorting-associated protein 4 (VPS4) — which can mediate different membrane fission events. ESCRTs machinery is also involved in protein sorting and endosomal intralumenal vesicle formation.

ER-associated degradation

A protein quality control system to degrade misfolded proteins of the endoplasmic reticulum (ER). These misfolded proteins are retrotranslocated through the ER membrane and are ubiquitylated by a membrane-associated ubiquitin E3 ligase complex. After ubiquitylation, these substrates are extracted from the ER membrane in an ATP-dependent manner and released to the cytosol for degradation by the proteasome.

ER whorls

During endoplasmic reticulum (ER) stress, subdomains of the ER are stacked together to form multilamellar membrane whorl structures, which might be mediated by eukaryotic translation initiation factor 2α kinase 3 (EIF2AK3) and the coat protein complex II (COPII) machinery in mammalian cells.

LC3

(MAP1LC3). LC3 is a homologue of yeast Atg8. Cytosolic LC3-I can be conjugated to phosphatidylethanolamine to become LC3-II, which is frequently used as an autophagic marker. The LC3 family includes LC3A, LC3B, LC3B2 and LC3C, all of which are involved in the biogenesis of autophagosomes, in cargo recruitment and in the fusion of autophagosomes with lysosomes.

ER exit site

(ERES). A subdomain of the endoplasmic reticulum (ER) where the coat protein complex II (COPII)-positive buds are formed.

Translocon

Protein complex involved in the transport of polypeptides and/or proteins across membranes. On the endoplasmic reticulum membrane, SEC61 subunits including SEC61A, SEC61B and SEC61G form a core channel associated with different accessory factors, such as SEC62 and SEC63, through which proteins translocate through the endoplasmic reticulum membrane.

LC3-interating region

(LIR). WXXL-like sequences in proteins such as sequestosome 1 (SQSTM1) and BCL-2-interacting protein 3-like protein (BNIP3L) that mediate binding to ATG8-family proteins.

Micronuclei

Small isolated nuclei that contain chromosomes and/or their fragments within the nuclear envelope, which are not incorporated into the daughter nucleus after cell division and are susceptible to rupture and degradation.

Homotypic fusion and protein-sorting complex

(HOPS complex). A protein complex consisting of vacuolar protein sorting-associated protein 11 (VPS11), VPS16, VPS18, VPS33A, VPS39 and VPS41 that mediates the fusion of late endosomes with lysosomes.

LC3-associated phagocytosis

Phagocytosis in macrophages that needs the conjugation of microtubule-associated protein 1 light chain 3 (MAP1LC3; also known as LC3)-family proteins to the single-membrane phagosome to promote phagosome acidification and fusion with lysosomes. This process is involved in immune regulation and inflammatory responses.

UNC-51-like autophagy-activating kinase 1

(ULK1). A mammalian homologue of yeast Atg1 which is required for macroautophagy to initiate the formation of the phagophore, and to recruit and release other autophagy-related proteins from the phagophore assembly site.

Intralumenal vesicles

Vesicles that are formed through invagination of the endosomal membrane or another membrane and hence reside within the lumen of the corresponding compartment.

ATG5

The gene encoding the protein ATG5, which is member of the ATG12–ATG5–ATG16L1 complex, which functions partly as an E3 ligase for ATG8-family protein conjugation to phosphatidylethanolamine.

Kufor-Rakeb syndrome

A rare form of inherited juvenile-onset atypical Parkinson disease, also known as Parkinson disease 9. Individuals with Kufor-Rakeb syndrome usually start to develop symptoms between 10 years and 20 years of age. In addition to the typical Parkinson disease symptoms, patients with Kufor-Rakeb syndrome can also experience atypical symptoms, such as supranuclear gaze palsy, paraplegia and ataxia.

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Wang, L., Klionsky, D.J. & Shen, HM. The emerging mechanisms and functions of microautophagy. Nat Rev Mol Cell Biol 24, 186–203 (2023). https://doi.org/10.1038/s41580-022-00529-z

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