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The cellular autophagy/apoptosis checkpoint during inflammation

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Abstract

Cell death is a major determinant of inflammatory disease severity. Whether cells live or die during inflammation largely depends on the relative success of the pro-survival process of autophagy versus the pro-death process of apoptosis. These processes interact and influence each other during inflammation and there is a checkpoint at which cells irrevocably commit to either one pathway or another. This review will discuss the concept of the autophagy/apoptosis checkpoint and its importance during inflammation, the mechanisms of inflammation leading up to the checkpoint, and how the checkpoint is regulated. Understanding these concepts is important since manipulation of the autophagy/apoptosis checkpoint represents a novel opportunity for treatment of inflammatory diseases caused by too much or too little cell death.

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Abbreviations

PAMPs:

Pathogen-associated molecular pattern molecules

LPS:

Lipopolysaccharide

TNF-α:

Tumor necrosis factor alpha

IL-1:

Interleukin-1

IFN-γ:

Interferon-gamma

DAMPs:

Damage-associated molecular pattern molecules

HMGB1:

High mobility group box-1

ATP:

Adenosine triphosphate

FasL/CD95L:

Fas ligand

TRAIL/Apo2L:

TNF-related apoptosis-inducing ligand

TL1A:

TNF-like ligand 1A

TLR:

Toll-like receptors

NOD:

Nucleotide-oligomerization domain

NLR:

NOD-like receptors

AIM2:

Absent in melanoma-2

ALRs:

AIM2-like receptors

CLR:

C-type lectin receptors

RIG-1:

Retinoic acid-inducible gene-I

RLR:

RIG-I-like receptors

TIR:

Toll/interleukin-1 receptor

MyD88:

Myeloid differentiation primary-response protein 88

MAPKs:

Mitogen-activated protein kinases

NF-κB:

Nuclear factor-kappa B

TRIF/TICAM1:

TIR-domain-containing adaptor protein inducing IFN-β

MDA5:

Melanoma differentiation-associated gene 5

LGP2:

Laboratory of genetics and physiology 2

DD:

Death domain

TRADD:

TNF-receptor-associated death domain

FADD:

Fas-associated DD

SOCS1:

Suppressor of cytokine signaling-1

ER:

Endoplasmic reticulum

PDI:

Protein disulfide isomerase

UPR:

Unfolded protein response

GRP78/BiP/HSPA5:

Glucose-regulated protein 78

PERK:

PKR-like ER kinase

IRE1:

Inositol requiring enzyme 1

ATF6:

Activation transcription factor 6

ERAD:

ER-associated degradation

ROS:

Reactive oxygen species

Nrf2:

NF-E2-related factor 2

TNFAIP3/A20:

Tumor necrosis factor, alpha-induced protein 3

mTOR:

Mammalian target of rapamycin

CoA:

Coenzyme A

S1P:

Sphingosine-1-phosphate

PE:

Phosphatidylethanolamine

CaMKK-β:

Calmodulin-dependent kinase kinase beta

AMPK:

AMP kinase

PCD:

Programmed cell death

TRAF2:

TNF-receptor-associated factor 2

cIAP1 or cIAP2:

Cellular inhibitors of apoptosis

LUBAC:

Linear ubiquitin chain assembly complex

TAK1:

TGF-activated kinase 1

TAB:

TAK1-binding protein

cFLIP:

Cellular FLICE-like inhibitory protein

MLKL:

Mixed lineage kinase domain-like

DISC:

Death-inducing signaling complex

MOMP:

Mitochondrial outer membrane permeabilization

Apaf-1:

Apoptosis protease activating factor-1

BH3:

Bcl-2-homology 3

Smac/DIABLO:

Second mitochondria-derived activator of caspase/direct IAP-binding protein with low PI

HtrA2/OMI:

Serine protease high-temperature requirement protein A2

IAPs:

Inhibitor of apoptosis proteins

UVRAG:

UV irradiation resistance-associated gene

DAPK:

Death-associated protein kinase

DRP:

DAPK-related proteins kinase

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Acknowledgements

Funding was provided by Crohn’s and Colitis Foundation of America and National Institute of Diabetes and Digestive and Kidney Diseases (Grant Nos. http://dx.doi.org/10.13039/100001063, P30 DK42086).

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  1. Department of Medicine, Knapp Center for Biomedical Discovery, University of Chicago, 900 E. 57th Street, 9th Floor, Chicago, IL, 60637, USA

    Jeannette S. Messer

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Messer, J.S. The cellular autophagy/apoptosis checkpoint during inflammation. Cell. Mol. Life Sci. 74, 1281–1296 (2017). https://doi.org/10.1007/s00018-016-2403-y

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