Canonical and Noncanonical Autophagy Pathways in Microglia - PubMed (original) (raw)

Review

. 2021 Feb 23;41(3):e0038920.

doi: 10.1128/MCB.00389-20. Epub 2020 Nov 2.

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Review

Canonical and Noncanonical Autophagy Pathways in Microglia

Julia Jülg et al. Mol Cell Biol. 2021.

Abstract

Besides the ubiquitin-proteasome system, autophagy is a major degradation pathway within cells. It delivers invading pathogens, damaged organelles, aggregated proteins, and other macromolecules from the cytosol to the lysosome for bulk degradation. This so-called canonical autophagy activity contributes to the maintenance of organelle, protein, and metabolite homeostasis as well as innate immunity. Over the past years, numerous studies rapidly deepened our knowledge on the autophagy machinery and its regulation, driven by the fact that impairment of autophagy is associated with several human pathologies, including cancer, immune diseases, and neurodegenerative disorders. Unexpectedly, components of the autophagic machinery were also found to participate in various processes that do not involve lysosomal delivery of cytosolic constituents. These functions are defined as noncanonical autophagy. Regarding neurodegenerative diseases, most research was performed in neurons, while for a long time, microglia received considerably less attention. Concomitant with the notion that microglia greatly contribute to brain health, the understanding of the role of autophagy in microglia expanded. To facilitate an overview of the current knowledge, here we present the fundamentals as well as the recent advances of canonical and noncanonical autophagy functions in microglia.

Keywords: LC3-associated endocytosis; LC3-associated phagocytosis; canonical autophagy; microglia; neurodegeneration; noncanonical autophagy.

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Figures

FIG 1

FIG 1

Autophagy pathway. The energy sensors mTORC1 and AMPK control autophagy activation via the ULK1 complex. Following activation, the ULK1 and PI3KC3 complex regulate the formation of the omegasome, and cargo is then recruited by autophagic receptors to the phagophore. Finally, the mature autophagosome fuses with lysosomes to autolysosomes, and the cargo is degraded.

FIG 2

FIG 2

Overview of phagocytosis, LC3-associated phagocytosis (LAP), LC3-associated endocytosis (LANDO), and clathrin-mediated endocytosis. (A) During phagocytosis, large extracellular particles are recognized by specific receptors, engulfed by the plasma membrane, and finally internalized by phagosomes. (B) When LC3 is recruited via the PI3KC3 II complex and other autophagy proteins to the phagosome before its fusion with the lysosome, the pathway is referred to as LAP. (C) When conjugation of LC3 by autophagy proteins to Rab5- and clathrin-positive endosomes is necessary for receptor recycling, the pathway is called LANDO. (D) Clathrin-mediated endocytosis describes the uptake of smaller extracellular cargo into clathrin-coated vesicles. After uncoating, the nascent vesicle is further transported within the cell, for example, to the sorting endosome.

FIG 3

FIG 3

Selective autophagy as a possible regulator of inflammasome activity in microglia. Presence of Aβ causes activation of proinflammatory response and release of the cytokine IL-1β. Autophagy receptors p62 and NDP52 might recognize and target ubiquitinated inflammasomes for lysosomal degradation, thereby controlling Aβ-induced inflammation and survival of the cell.

FIG 4

FIG 4

Canonical and noncanonical autophagy functions associated with neurological diseases. The inner and outer circles present canonical and noncanonical autophagy processes, respectively. So far, these pathways were most extensively studied in neurodegenerative diseases. However, only little is known about their functions in neuropsychological diseases. Further aspects remain to be identified. Concerning neuroinfectious diseases, either canonical xenophagy or LAP can eliminate the invading particle, depending on its pathogenic characteristics.

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