Tài liệu Báo cáo khoa học: ER stress and diseases docx

REVIEW ARTICLE

ER stress and diseases

Hiderou Yoshida1,2

1 Department of Biophysics, Graduate School of Science, Kyoto University, Japan

2 PRESTO-SORST, Japan Science and Technology Agency, Japan

Keywords

conformational disease; cytoplasmic splicing;

ER stress response; ER-associated protein

degradation (ERAD); Golgi stress response

Correspondence

H. Yoshida, Department of Biophysics,

Graduate School of Science, Kyoto

University, Kitashirakawa-Oiwakecho,

Sakyo-ku, Kyoto 606-8502, Japan

Fax: +81 75 753 3718

Tel: +81 75 753 4201

E-mail: [email protected].

kyoto-u.ac.jp

(Received 11 September 2006, revised

14 November 2006, accepted 8 December

2006)

doi:10.1111/j.1742-4658.2007.05639.x

Proteins synthesized in the endoplasmic reticulum (ER) are properly folded

with the assistance of ER chaperones. Malfolded proteins are disposed of

by ER-associated protein degradation (ERAD). When the amount of

unfolded protein exceeds the folding capacity of the ER, human cells acti￾vate a defense mechanism called the ER stress response, which induces

expression of ER chaperones and ERAD components and transiently

attenuates protein synthesis to decrease the burden on the ER. It has been

revealed that three independent response pathways separately regulate

induction of the expression of chaperones, ERAD components, and trans￾lational attenuation. A malfunction of the ER stress response caused by

aging, genetic mutations, or environmental factors can result in various dis￾eases such as diabetes, inflammation, and neurodegenerative disorders

including Alzheimer’s disease, Parkinson’s disease, and bipolar disorder,

which are collectively known as ‘conformational diseases’. In this review, I

will summarize recent progress in this field. Molecules that regulate the ER

stress response would be potential candidates for drug targets in various

conformational diseases.

Abbreviations

AIGP, axotomy-induced glyco ⁄ Golgi protein; APP, amyloid precursor protein; ASK1, apoptosis signal-regulating kinase 1; ATF, activating

transcription factor; BAK, Bcl-2 homologous antagonist ⁄ killer; BAP, BiP-associated protein; Bap31, B cell receptor-associated protein 31; Bax,

Bcl2-associated X protein; Bcl2, B cell leukemia 2; BI-1, Bax inhibitor 1; Bim, Bcl2-interacting mediator of cell death; BiP, binding protein; bZIP,

basic leucine zipper; c-Abl, Abelson murine leukemia viral oncogene homolog 1; C ⁄ EBP, CCAAT ⁄ enhancer-binding protein; CHOP, C ⁄ EBP￾homologous protein; CREB, cAMP response element-binding protein; CREBH, cAMP response element-binding protein H; CReP, constitutive

repressor of eIF2a phosphorylation; DAP, death-associated protein; Der1, degradation in the endoplasmic reticulum protein 1; Derlin-1, Der1-

like protein 1; Doa10, degradation in the endoplasmic reticulum protein 10; DR5, death receptor 5; EDEM, ER degradation enhancing

a)mannosidase-like protein; eIF2 a, a-subunit of eukaryotic translational initiation factor 2; ER, endoplasmic reticulum; ERAD, ER-associated

degradation; ERdj, ER dnaJ; ERO1, ER oxidoreductin; ERp72, ER protein 72; ERSE, ER stress response element; FKBP13, FK506-binding

protein 13; GADD, growth arrest and DNA damage; gp78, glycoprotein 78; GRP, glucose-regulated protein; HEDJ, human ER-associated dnaJ;

HIAP2, human inhibitor of apoptosis 2; HRD1, HMG-CoA reductase degradation protein 1; HSP, heat shock protein; IAP, inhibitor of apoptosis;

IDDM, insulin-dependent diabetes mellitus; IRE1, inositol requirement 1; JNK, Jun kinase; Keap1, Kelch-like Ech-associated protein 1; LZIP,

basic leucine zipper protein; NIDDM, noninsulin-dependent diabetes mellitus; NOXA, neutrophil NADPH oxidase factor; Npl4, nuclear protein

localization 4; NRF, nuclear respiratory factor; ORP150, oxygen-regulated protein 150; OS9, osteosarcoma 9; p58IPK, 58 kDa-inhibitor of

protein kinase; pATF6(N), the nuclear form of ATF6 protein; PDI, protein disulfide isomerase; PERK, PRKR-like endoplasmic reticulum kinase;

PKR, double stranded RNA-dependent protein kinase; PLP1, proteolipid protein 1; polyQ, polyglutamine; PrP, pion protein; PrPc

, cellular PrP;

PrPSc, scrapie PrP; PS1, presenillin 1; PUMA, p53 up-regulated modulator of apoptosis; pXBP1(S), the spliced form of XBP1 protein; pXBP1(U),

the unspliced form of XBP1 protein; RIP, regulated intramembrane proteolysis; RseA, regulator of sE

; S1P, site 1 protease; S2P, site 2

protease; SAPK, stress-activated protein kinase; SEL1, suppressor of lin12-like; SREBP, sterol response element-binding protein; TDAG51,

T cell death-associated gene 51; TNF, tumor necrosis factor; TNFR1, tumor necrosis factor receptor 1; TRAF2, TNF receptor-associated

factor 2; TRB3, Tribbles homolog 3; UBC6, ubiquitin conjugase 6; UBC7, ubiquitin conjugase 7; UBE1, ubiquitin-activating enzyme 1; UBE2G2,

ubiquitin-activating enzyme 2G2; UBX2, UBX domain-containing protein 2; UCH-L1, ubiquitin C-terminal esterase L1; Ufd1, ubiquitin fusion

degradation protein 1; UPRE, unfolded protein response element; VCP, valocin-containing protein; WFS1, Wolfram syndrome 1; XBP1, x-box

binding protein 1; XIAP, inhibitor of apoptosis, x-linked; XTP3B, XTP3-transactivated gene B.

630 FEBS Journal 274 (2007) 630–658 ª 2007 The Author Journal compilation ª 2007 FEBS

Introduction

The endoplasmic reticulum (ER) is an organelle where

secretory or membrane proteins are synthesized. Nas￾cent proteins are folded with the assistance of molecu￾lar chaperones and folding enzymes located in the ER

(collectively called ER chaperones), and only correctly

folded proteins are transported to the Golgi apparatus

(Fig. 1). Unfolded or malfolded proteins are retained

in the ER, retrotranslocated to the cytoplasm by the

machinery of ER-associated degradation (ERAD), and

degraded by the proteasome. ER chaperones and

ERAD components are constitutively expressed in the

ER to deal with nascent proteins. When cells synthes￾ize secretory proteins in amounts that exceed the capa￾city of the folding apparatus and ERAD machinery,

unfolded proteins are accumulated in the ER. Unfol￾ded proteins expose hydrophobic amino-acid residues

that should be located inside the protein and tend to

form protein aggregates. Protein aggregates are so

toxic that they induce apoptotic cell death and cause

‘conformational diseases’ such as neurodegenerative

disorders and diabetes mellitus. To alleviate such a

stressful situation (ER stress), eukaryotic cells activate

a series of self-defense mechanisms referred to collec￾tively as the ER stress response or unfolded pro￾tein response [1–4].

The mammalian ER stress response consists of four

mechanisms. The first is attenuation of protein synthe￾sis, which prevents any further accumulation of un￾folded proteins. The second is the transcriptional

induction of ER chaperone genes to increase folding

capacity, and the third is the transcriptional induction

of ERAD component genes to increase ERAD ability.

The fourth is the induction of apoptosis to safely dis￾pose of cells injured by ER stress to ensure the survival

of the organism.

In this article, I will describe the basics of the mam￾malian ER stress response that are essential to under￾standing conformational diseases. I will review hot

topics such as ERAD, regulated intramembrane pro￾teolysis (RIP) and cytoplasmic splicing, and briefly

summarize the ER stress-related diseases.

ER stress-inducing chemicals

Chemicals such as tunicamycin, thapsigargin, and

dithiothreitol are usually used to evoke ER stress in

cultured cells or animals for experimental purposes. I

will briefly summarize the ER stress-inducing chemicals

below.

The first group of ER stressors comprises glycosyla￾tion inhibitors. Most of the proteins synthesized in

the ER are N-glycosylated, and the N-glycosylation is

cytoplasm

ER

ER chaperone

degraded

ribosome mRNA

unfolded protein

aggregation

ER stresss

nascent protein

Golgi apparatus

apoptosis folding disease

ERAD

translational attenuation

Fig. 1. Mammalian ER stress response. An accumulation of unfolded proteins in the ER evokes ER stress, and cells induce the ER stress

response to cope. The mammalian ER stress response consists of four mechanisms: (1) translational attenuation; (2) expression of ER chap￾erones; (3) enhanced ERAD; (4) apoptosis.

H. Yoshida ER stress and diseases

FEBS Journal 274 (2007) 630–658 ª 2007 The Author Journal compilation ª 2007 FEBS 631