Autophagy in inflammation, infection, and immunometabolism

Deretic, Vojo

doi:10.1016/j.immuni.2021.01.018

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Deretic, V. (2021). Autophagy in inflammation, infection, and immunometabolism. Immunity, 54(3), 437–453.
Added by: Dr. Enrique Feoli (16/04/2023, 19:55) Last edited by: Dr. Enrique Feoli (17/04/2023, 18:28)

Resource type: Journal Article
DOI: 10.1016/j.immuni.2021.01.018
ID no. (ISBN etc.): 1074-7613
BibTeX citation key: Deretic2021
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Categories: BioAcyl Corp, BioAcyl Corp, BioAcyl Corp
Subcategories: Autophagy and mitophagy, Constitutive innate immunity, Immunometabolism
Creators: Deretic
Collection: Immunity

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Abstract

{Autophagy is a quality-control, metabolic, and innate immunity process. Normative autophagy affects many cell types, including hematopoietic as well as non-hematopoietic, and promotes health in model organisms and humans. When autophagy is perturbed, this has repercussions on diseases with inflammatory components, including infections, autoimmunity and cancer, metabolic disorders, neurodegeneration, and cardiovascular and liver diseases. As a cytoplasmic degradative pathway, autophagy protects from exogenous hazards, including infection, and from endogenous sources of inflammation, including molecular aggregates and damaged organelles. The focus of this review is on the role of autophagy in inflammation, including type I interferon responses and inflammasome outputs, from molecules to immune cells. A special emphasis is given to the intersections of autophagy with innate immunity, immunometabolism, and functions of organelles such as mitochondria and lysosomes that act as innate immunity and immunometabolic signaling platforms.}

Notes

(A) Lysosomal integrity is maintained by a system termed MERiT (membrane repair, removal, and replacement). Galectins (Gal3, Gal8, and Gal9) recognize β-galactoside glycans exposed on cognate lysosomal membrane proteins: TFRC (transferrin receptor), SLC38A9, and LAMP1 and LAMP2 (not depicted) when lysosomal membrane is breached. They stimulate ESCRTs to repair lysosomes and AMPK to activate autophagy, whereas mTOR is inactivated. TRIM16 is one of lysophagy receptors. TFEB starts transcriptional program to replace lysosomes.

(B) Lysosome as the hub for AMPK, mTOR, and TFEB, the three master regulators of autophagy, lysosomal system, metabolism, and immunometabolism. Inhibitory and activating relationships are indicated and include TBK1 (which has positive and negative regulatory connections with AMPK and mTOR).

(D) Mitophagy, mitophagy receptors, and mitophagic suppression of inflammation caused by mitochondrial DAMPs (mito-DAMPs). Dashed lines separate different types of mitophagy and proinflammatory signaling from damaged mitochondria. Top, Pink1-Parkin system and receptors that participate in removal of dysfunctional mitochondria. Pink1 kinase and Parkin E3 ligase (phosphorylated by Pink1 to activate latent Parkin activity and recruit it to mitochondria) lead to ubiquitination and generation of phospho-ubiquitin which further amplifies Parkin activity leading to recognition of depolarized or damaged mitochondria by SLRs, NDP52 and OPTN, which bind ubiquitin. Bottom left, other mitophagy receptors act as integral membrane proteins of mitochondria and participate in mitophagy under developmental, differentiation, or stress conditions.

(E) Molecular machinery involved in STING-TBK1 activation in response to ectopic dsDNA, e.g., mitochondrial DNA that leaks into the cytosol (see D), DNA from pathogens (viruses and bacteria), etc. dsDNA binds to and stimulates cGAS that enzymatically generates cGAMP. STING stimulated by cGAMP (and other cyclic dinucleotides that may come from bacteria) activates TBK1.

(F) TBK1 phosphorylates SLRs modulating their ability to bind ubiquitin and mAtg8s such as LC3B and possibly affecting other interactions.

G) TBK1 phosphorylates Syntaxin 17 (Stx17) involved in mPAS (mammalian pre-autophagosomal structure) and subsequent stages such as maturation. (H) TBK1 phosphorylates two members of the mAtg8 family rendering them resistant to delipidation by ATG4.

Added by: Dr. Enrique Feoli Last edited by: Dr. Enrique Feoli