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Look who’s talking—the crosstalk between oxidative stress and autophagy supports exosomal-dependent release of HCV particles

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Abstract

Autophagy is a highly conserved and regulated intracellular lysosomal degradation pathway that is essential for cell survival. Dysregulation has been linked to the development of various human diseases, including neurodegeneration and tumorigenesis, infection, and aging. Besides, many viruses hijack the autophagosomal pathway to support their life cycle. The hepatitis C virus (HCV), a major cause of chronic liver diseases worldwide, has been described to induce autophagy. The autophagosomal pathway can be further activated in response to elevated levels of reactive oxygen species (ROS). HCV impairs the Nrf2/ARE-dependent induction of ROS-detoxifying enzymes by a so far unprecedented mechanism. In line with this, this review aims to discuss the relevance of HCV-dependent elevated ROS levels for the induction of autophagy as a result of the impaired Nrf2 signaling and the described crosstalk between p62 and the Nrf2/Keap1 signaling pathway. Moreover, autophagy is functionally connected to the endocytic pathway as components of the endosomal trafficking are involved in the maturation of autophagosomes. The release of HCV particles is still not fully understood. Recent studies suggest an involvement of exosomes that originate from the endosomal pathway in viral release. In line with this, it is tempting to speculate whether HCV-dependent elevated ROS levels induce autophagy to support exosome-mediated release of viral particles. Based on recent findings, in this review, we will further highlight the impact of HCV-induced autophagy and its interplay with the endosomal pathway as a novel mechanism for the release of HCV particles.

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Abbreviations

AMPK:

AMP-Activated protein kinase

ARE:

Antioxidant response element

ATF6:

Activating transcription factor 6

Atg:

Autophagy-related genes

CHO:

Chinese hamster ovary

CMA:

Chaperone-mediated autophagy

cPLA2:

Cytosolic phospholipase A2

CYP2E1:

Cytochrome P450 2E1

DGAT-1:

Diacylglyceroltransferase

DMV:

Double-membrane vesicles

DFCP1:

Double FYVE-containing protein 1

EE:

Early endosome

eIF2α:

Eukaryotic translation initiation factor 2α

ER:

Endoplasmatic reticulum

ERGIC:

ER-Golgi intermediate compartment

Ero1:

ER oxidoreductins

ESCRT:

Endosomal sorting complexes required for transport

HCC:

Hepatocellular carcinoma

HCV:

Hepatitis C virus

HOPS:

Homotypic fusion protein sorting

Hrs:

Hepatocyte growth factor-regulated tyrosine kinase substrate

IFN:

Interferon

ILV:

Intraluminal vesicle

IMM:

Inner mitochondrial membrane

IRE1:

Inositol-required protein 1

KIR:

Keap1-interacting region

LC3:

Microtubule-associated protein 1 light chain 3

LD:

Lipid droplets

LE:

Late endosome

LIR:

LC3-interacting region

MLBs:

Multilamellar bodies

MPT:

Mitochondrial permeability transition

mPTP:

Mitochondrial permeability transition pore

mTOR:

Mammalian target of rapamycin

MVB:

Multivesicular body

MW:

Membranous web

M6PR:

Mannose-6-phosphate receptor

NOX:

NADPH oxidase

NS:

Non-structural

NSF:

N-ethylmaleimide-sensitive factor

OMM:

Outer mitochondrial membrane

ORP1L:

Oxysterol-binding protein-related protein 1L

PAS:

Phagophore assembly sites

pDC:

Plasmacytoid dendritic cells

PDI:

Protein disulfide isomerase

PE:

Phosphatidylethanolamine

PERK:

Protein kinase (PKR)-like ER kinase

PI3P:

Phosphatidylinositol-3-phosphate

PI4KA:

Phosphatidylinositol-4-kinase IIIα

PLEKHM1:

Pleckstrin homology domain-containing family M member 1

PM:

Plasma membrane

RC:

Replicon complex

RE:

Recycling endosome

RILP:

Rab-interacting lysosomal protein

ROS:

Reactive oxygen species

SERCA:

Sarcoplasmic/endoplasmic reticulum calcium ATPase

SNAP:

Soluble NSF attachment protein

SNAP25:

25 kDa synaptosome-associated protein

SNARE:

Soluble N-ethylmaleimide-sensitive factor attachment receptor

Stx:

Syntaxin

Tfn:

Transferrin

TfnR:

Tfn receptor

TGN:

trans-Golgi network

TIP47:

Tail-interacting protein of 47 kDa

TMD:

Transmembrane domain

Tsg101:

Tumor susceptibility gene 101

Txlna:

α-Taxilin

UBA:

Ubiquitin-associated domain

UPR:

Unfolded protein response

VAMP:

Vesicle-associated membrane protein

VDAC:

Voltage-dependent anion channel

VLDL:

Very low-density lipoproteins

Vps4:

Vascular protein sorting 4

WIPI:

WD-repeat domain phosphoinositide-interacting protein

XBP1:

X-box binding protein 1

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Authors and Affiliations

  1. Department of Virology, Paul-Ehrlich-Institut, Paul-Ehrlich-Straße 51–59, 63225, Langen, Germany

    Regina Medvedev, Eberhard Hildt & Daniela Ploen

  2. Deutsches Zentrum für Infektionsforschung (DZIF), Gießen, Marburg, Langen, Germany

    Eberhard Hildt

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  1. Regina Medvedev
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Medvedev, R., Hildt, E. & Ploen, D. Look who’s talking—the crosstalk between oxidative stress and autophagy supports exosomal-dependent release of HCV particles. Cell Biol Toxicol 33, 211–231 (2017). https://doi.org/10.1007/s10565-016-9376-3

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