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1 Journal of Bacteriology and Virology Vol. 42, No. 3 p Review Article Endoplasmic Reticulum Stress Responses and Apoptosis Chang-Hwa Song * Department of Microbiology and Research Institute for Medical Sciences, College of Medicine, Chungnam National University, Daejeon, Korea The endoplasmic reticulum (ER) plays a crucial role in various cellular activities and cell survival. Almost all of the resident proteins usually enter the ER, and are modified with N-linked glycans and folded into the appropriate secondary and tertiary structures. When cells are faced with stressful conditions, unfolded proteins are accumulated in the ER. The discrepancies between the protein folding capacities and client protein load lead to ER stress. If the stress is prolonged, ER stress responses can activate apoptosis. ER stress-mediated apoptosis is implicated in the pathophysiology of human diseases, including several neurodegenerative diseases, diabetes mellitus, and various infectious diseases. Thus, the ER is now considered as an important organelle that can decide cell survival or death. In this review, the recent progress on ER stress and apoptosis is summarized. Key Words: ER stress, Apoptosis, Organelle 서론 소포체는필수적인세포소기관으로핵막으로부터뻗어나와가지친모양의막성분구조물이다. 소포체는표면에리보솜이붙어있는조면소포체 (rough endoplasmic reticulum) 와리보솜이없는활면소포체 (smooth endoplasmic reticulum) 로나누어분류한다. 소포체는단백질합성뿐아니라 N-linked glycan의첨가나 disulfide bond 형성을통해단백질의수정 (modification) 과접힘 (folding) 을완성하고지질이나스테롤을합성하며칼슘저장소로서의기능을수행한다 (1~3). 단백질의수정이나접힘의과정은세 Received: May 27, 2012/ Revised: June 27, 2012 Accepted: July 2, 2012 * Corresponding author: Dr. Chang-Hwa Song. Department of Microbiology, College of Medicine, Chungnam National University, 6 Munhwa-dong, Junggu, Daejeon , Korea. Phone: , Fax: songch@cnu.ac.kr ** This work was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology ( ), and by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (No ). 포의생존에필수적이며소포체에서는단백질을원하는기능에맞도록수정하거나접히게하여골지체로운반할수있도록한다. 하지만이러한과정이특정생리적조건하의다양한상황, 예를들면소포체가처리할수있는능력이상의미성숙단백질이소포체내로유입되거나, 소포체내에돌연변이단백질의축적이일어난다거나, 또는칼슘고갈과같은병리적조건등에의해교란될수있다. 이런세포내의불균형을감지하거나반응하는것을일컬어소포체스트레스라고하며종합적으로는미접힘단백질반응, 즉 unfolded protein response (UPR) 라고하는진핵세포내에발전된특별한세포신호경로를말한다. 세포자멸사 (apoptosis) 는진핵세포생물의발달과정에포함되어있는정상적인과정인데세포가다양한자극에대해반응할때조절되고제어된형태로진행되는세포의죽음이다 (4). 일반적으로세포자멸사는두가지주된경로에의해나누어볼수있다. 하나는 death receptor의상호작용을포함하고있으며다른하나는미토콘드리아가관여한다. 그외또다른경로로서는소포체스트레스에의한세포자멸사반응을들수있다. 이것과관련하여많은연구자들은세균감염시숙주세포로부터발생 196

2 Endoplasmic Reticulum Stress Responses and Apoptosis 197 하는세포자멸사역할이숙주방어에매우중요할것으로생각한다. 본논문에서는현재까지알려진소포체스트레스반응과세포자멸사와의상호관계와기능에대해알아보고자한다. 본론 1. 소포체스트레스에의해유도되는세포생존소포체스트레스는정상적인소포체의기능에교란이생길때유발되는것으로서미접힘단백질이나잘못접힘단백질, 또는과다한단백질이축적될때, 소포체내지질과 glycolipid의불균형, 산화환원이나이온농도변화등의스트레스요인에의해발생한다 (5). 세포에서발생하는소포체스트레스는단백질합성과접힘을위한소포체의기능향상, 소포체내단백질의감소등과같이소기관의부담을덜어주는쪽으로작동한다 (6). 즉, 샤페론단백질의발현을증가시켜소포체의접힘능력을향상시키거나단백질합성을억제시킴으로써세포내스트레스요인을제거하려고한다. 소포체스트레스가미접힘단백질반응을활성화하는것은세가지소포체막통과신호전달물질들, 즉 protein kinase PKR-like ER kinase (PERK), inositol requiring 1 (IRE1), activating transcription factor 6 (ATF6) 을통해수행된다 (Fig. 1) (6). 그외에소포체내단백질접힘능력을증가시켜스트레스를완화시키는세포내작동인자들로는 GRP78/BIP, GRP94, protein disulfide isomerase 를포함한효소와 peptidyl-prolyl isomerase, 그리고 sarcoplasmic ER Ca 2+ -ATPase 2 (SERCA2) 와같은소포체샤페론단백질들을예로들수있다 (2). 각각의알려진기능에대해살펴보면, IRE1은소포체막에존재하는 endornase로서스트레스가없는조건에서는 BIP와결합하여비활성화상태로존재하다가소포체스트레스발생시, 결합되어있던 BIP가떨어져나가면서인산화되어활성화된다. 이렇게활성화된 IRE1은 X-box binding protein-1 (XBP-1) 이라고하는전사인자의 mrna을 splicing시켜활성화된 XBP-1 형태가되도록유도한다. 활성화된 XBP-1은 ER stress response element에결합하여전사활성을유발한다 (7). ATF6은소포체막에존재하는전사인자로서 C-말단부분은소포체쪽에있고, 전사활성영역을지닌 N-말단은세포질쪽에위치한다 (8). 소포체스트레스발생시 ATF6 는골지체쪽으로이동한후 site-1 protease (S1P) 와 site-2 protease (S2P) 에의해절단되어 p50인 N-말단 ATF6 (p90) 가핵으로이동하여전사인자로작용한다. 이를통해단백질접힘에관련하는효소와샤페론의발현을유도하는것으로알려져있다 (8, 9). PERK는소포체막에위치한 type 1 transmembrane serine/threonine kinase로서다른샤페론단백질과마찬가지로스트레스가없는조건에서는 BIP와결합해존재하다가잘못접힌단백질의증가와같은스트레스상황에서 BIP가떨어져나가활성화되면 eukaryotic translation initiation factor 2 alpha (eif2α) 를인산화한다. 인산화된 eif2α는번역개시복합체의구성인자로서리보솜의개시자코돈인 AUG에 methionine을운반하는역할을수행하는데, 인산화될때불활성화되면 mrna로부터단백질로의번역이감소하여소포체내로의새로운단백질유입이감소하여세포가스트레스로부터벗어나도록한다 (1, 10, 11). 세포의스트레스반응초기에는아미노산을들여오거나, 글루타치온생합성, 산화적스트레스에대한세포의보호작용등에관련된일련의유전자들의발현이증가하는데, 후기에는 ER degradation-enhancing α-mannosidaselike protein (EDEM) 을포함한 ER-associated degradation (ERAD) 의성분들이 ubiquitin-proteasome system에의해소포체내에잘못접힘단백질을제거하기위해증가된다 (11, 12). 2. 소포체스트레스에의해유도되는세포자멸사소포체에존재하는 IRE1, PERK, ATF6 의신호전달과정은세포의생존에관련되어있을뿐만아니라세포자멸사과정에도관여하는데세포에대한스트레스상황이매우강하거나지속적으로일어나면소포체의기능이비정상적으로작용하여세포자멸사가유도된다. 단백질의분비가급격히증가되는생리적인스트레스, 잘못접힌단백질의존재나세포내칼슘의고갈과같은병리적스트레스는단백질접힘을위한필요와소포체의처리능력간의불균형을초래하게되어소포체스트레스를유발할수있다. 소포체스트레스반응은미접힘단백질반응을활성화시켜새로운단백질합성의중단, folding enzyme이나소포체샤페론의생성증가, 소포체관련분해작용의증가가일어난다 (6). 그러나소포체스트레스의지속적이고강력한반응은세포자멸사를유도할수있는데소포체스트레스에의한세포자멸사

3 198 C-H Song Figure 1. ER stress response and apoptosis. On ER stress, IRE1, PERK, and ATF6 proteins initiate signal transduction that controls cell survival or death. There are at least three different mechanisms to induce ER stress; translational attenuation to avoid further accumulation of misfolded ER proteins; transcriptional activation of genes encoding ER-resident molecular chaperones; and the ER-associated degradation (ERAD) pathway to restore the folding capacity. If the cells are exposed to prolonged and strong ER stress, the damaged cells are destroyed by apoptosis. 의유도에관여하는요소들로서는 C/EBP homologous protein (CHOP) 단백질, IRE-1 매개 ASK1/JNK의활성, procaspase-12의활성과 Bcl-2에의해조절되는소포체로부터칼슘의방출등이여기에포함된다 (2, 3). CHOP은 DNA damage-inducible gene 153 (GADD153) 이 라고도알려져있으며 CCAT/enhancer binding protein (C/EBPs) 중하나로서 29 kda 정도크기의단백질을암호화하고있는유전자독성신호나성장억제신호에의해발현되는유전자들중하나로알려져있다 (11, 13). CHOP 단백질 C-말단부위의 basic-leucine zipper 도메인

4 Endoplasmic Reticulum Stress Responses and Apoptosis 199 은 CHOP에의해유도되는세포자멸사에서중요하다 (11). 세포의생존이나죽음에관련되어있는 DOC1, DOC4, DOC6과같은유전자들은 CHOP의하위경로에있으며 CHOP에의해직접영향을받는다. 또한 CHOP 단백질의발현은 Bcl-2나 BIP의발현에의해서도저해받는다 (11). CHOP의발현으로소포체내고분자단백질복합체의축적을가져와소포체의기능이상실되고, Bax 를세포질에서미토콘드리아로이동시켜세포자멸사를유도한다 (13). CHOP은낮은농도로세포에산재되어있다가소포체스트레스에의해발현이증가되며, 소포체막에위치한 ATF6, IRE1, PERK와같은소포체스트레스반응의특징적인단백질들에의해활성화되고특히 PERK-eIF2α-ATF4 경로가 CHOP의발현에중요하며증가된 CHOP이세포자멸사를가져온다고알려졌다 (11). 또한 CHOP에의해유도되는세포자멸사의기전에는 Bcl-2, GADD34, endoplasmic reticulum oxidoreductin 1 (ERO1α) 와 tribbles-related protein 3 (TRB3) 같은유전자들이포함된다. 이들중 GADD34는 protein phosphatase1 (PP1) 과상호작용을통해 eif2α의탈인산화를유도하여전사를억제하며그결과세포자멸사를유도한다 (14). TRB3는또하나의 CHOP에의해유도되는유전자로서 TRB3의기능은 pro-survival serine/threonine kinase AKT에결합함으로써 AKT의인산화를막아 kinase의활성을감소시켜세포자멸사를유도한다 (15). CHOP 단백질은세포자멸사를유도할뿐만아니라다른 C/EBP를갖는단백질과 heterodimer를이루어 IL-1β의활성을유도하여염증반응에도관여한다 (16). Caspase 는대표적인 proapoptotic cysteine protease로서소포체스트레스에의해유도되는세포자멸사에중요한역할을수행한다. 특히 caspase-12는설치류에서발견되는단백질로서소포체내에존재하며소포체스트레스에의해활성화된다. 활성화된 caspase-12는 caspase-9 의활성화를유도하고, caspase-9에의해 caspase-3의활성화가일어나면세포자멸사가유도된다 (17, 18). Caspase-12는소포체스트레스에관련된성분에의한세포자멸사신호에의해활성화되지만소포체스트레스를유도하지않는세포자멸사신호에의해서는활성화되지않는것으로알려져소포체스트레스특이적세포자멸사유도에관련된분자적마커로사용될수있다 (18). Caspase-12를활성화시키는또다른경로로는소포체스트레스로증가된세포질내칼슘이유도한 m-calpain 의 활성을들수있다. 활성화된 m-calpain은 Bcl-XL을자르고 caspase-12를분해하여활성화한다 (20). Procaspase- 12는평소에는주로소포체에존재하지만소포체스트레스나세포질내칼슘온도의급격한변화와같은소포체항상성에교란이생기게되면활성화된다 (19). 사람에서 caspase-12의기능은설치류의 caspase-12와는다른것으로알려져있고 caspase-4 가설치류 caspase-12와 48% 정도의상동성이있는것으로보고되었다 (20). 소포체스트레스에의해유도되는세포사멸을가져오는마우스의 caspase-12처럼사람에서는 caspase-4 가유사한기능을수행하는것으로보고되었다 (20). IRE1은세포의생존을증진시키기위해 XBP-1의 mrna를 splicing함으로써미접힘단백질반응을유도하는기능을수행하는데, IRE1의세포생존에관련된기능에도불구하고 IRE1의과발현은전염증성사이토카인의신호전달경로에포함되어있는 TRAF2와의상호작용을통해 ASK1을불러와 IRE1/TRAF2/ASK1 복합체를형성하고이는 JNK의활성을가져오게되는데 JNK는 Bcl-2 family 단백질의조절을통해세포자멸사를유도한다 (17, 21). JNK는 Bcl-2의인산화시킬뿐만아니라 Bim과같은 BH3-only protein들을인산화시켜세포자멸사를유도할수있다. Bcl-2 family 단백질은미토콘드리아외막에서주로작용하는것으로알려져있다. Bcl-2는소포체막에작용하여소포체에존재하는 Bax와 Bak과같은세포자멸사유도단백질과결합하여소포체로부터칼슘이방출되는것을막고, 방출된칼슘이 calpain을활성화시켜 caspase- 12의활성을통해세포자멸사를유도하는것을방지하여세포자멸사를억제한다 (22, 23). 그외에도 Bax inhibitor-1 (BI-1) 라는단백질도소포체막에존재하여 Bcl-XL나 Bcl-2와상호작용하여소포체로부터의칼슘방출조절을통해세포자멸사에영향을주는것으로알려졌다 (24). 3. 바이러스의감염과소포체스트레스반응에의한세포자멸사진핵세포에대한바이러스의감염은세포내로침투, 핵산의발현, 폴리펩티드합성과수정, 유전자복제, 성숙등을포함한일련의과정들로이루어진다. 바이러스는숙주세포내에서자신의유전자를합성하며단백질을생성하는과정에서소포체스트레스반응을일으킨다.

5 200 C-H Song 바이러스감염시, 진핵세포에서인터페론에의해유도되는 double-stranded RNA-dependent protein kinase (PKR) 은 double-stranded RNA에의해활성화되는데, 활성화된 PKR이 eif2α의인산화를가져와단백질합성을막고바이러스복제의저해를가져온다 (25). eif2α의인산화는 activation transcription factor 4 (ATF4) 의발현을유도하여 CHOP이나 GADD34의발현을자극하여세포자멸사를가져온다. 소포체는단백질의번역후수정이나접힘을완성하는장소로서바이러스의증식과성숙에필수적이다. 바이러스에의해감염된세포내에서합성되는막대한양의바이러스단백질들은미접힘또는잘못접힘단백질을증가시키고그결과소포체스트레스를일으켜세포의생존과죽음을이끄는다양한신호경로를조절한다 (26, 27). 바이러스의감염에의한소포체내에바이러스단백질의생성은 BIP나 GRP94의발현을증가시킨다 (28, 29). 여러연구에서 BIP는바이러스 glycoprotein 의접힘중재자로서일시적인역할을하는것으로보고하였다 (28, 30). RNA 바이러스는바이러스의증식과성숙을위한장소로서소포체를사용하는데 PERK를조절하고다른몇몇바이러스는 ATF6 경로나 IRE1-XBP1 경로를조절함으로써바이러스의생존에적합한환경을조성하는것으로추정하지만구체적인기전에대해서는여전히알려지지않았다. 다만, 바이러스감염이소포체스트레스와밀접한관계를갖고있으므로소포체스트레스반응매개세포자멸사유도가바이러스감염시매우중요한생물학적의미가있을것으로생각한다. 4. 세균감염과소포체스트레스반응에의한세포자멸사바이러스감염에서미접힘단백질반응에관하여는여러가지연구결과들이보고되었지만세균의감염에대하여는거의알려진바가없다. 최근연구결과들중에서세포내기생세균중하나인 Listeria monocytogenes가소포체의확장과미접힘단백질반응을유도하는데 PERK 단백질활성을통해소포체스트레스를유발하며, 소포체스트레스유도체에의해세포내균수가감소하는것을제시하였다 (31). Mycobacterium tuberculosis와같은세포내기생세균역시 eif2α의인산화를억제시켜세포내생존환경을조절하는데소포체스트레스반응의증가는 M. tuberculosis의생존에불리할것으로보고되었다 (32). 그밖에 shiga toxin 이나 ESAT-6와같은세균분비항원에 의해소포체스트레스반응이유도되며이는세포자멸사와연관되어있다는연구보고들이잇따르고있다 (17, 33). 소포체는미토콘드리아, 골지체와같은세포소기관들과구조적으로나기능적으로밀접하게연관되어있다. 단백질의초기분비경로에관여하는 N-ethylmaleimidesensitive fusion protein (NSF)/SNARE나 sec7, sec12, sec16, sec23, sec24와같은 coat protein II vesicle budding factor류는소포체로부터단백질의방출이나골지체를통한이동에영향을주며, 최종적으로자가포식에도영향을미친다 (34). 이와같이소포체스트레스반응은생체내여러소기관들과신호경로들이복잡하게얽혀상호연관성을가지고있다. 따라서세균의감염에대한소포체, 골지체, 미토콘드리아와같은세포소기관들의반응에관한연구는이들세포소기관의기능을종합적으로이해하는것이세균에의한병리현상을규명하는데매우중요할것으로생각한다. 결론소포체는세포의항상성유지에매우중요한역할을수행하는세포소기관으로서소포체에서발생하는소포체스트레스반응은자가포식현상과유사하게세포의생존이나죽음에밀접하게연관되어있다. 따라서소포체스트레스는알츠하이머병, 파킨슨씨병, 암, 당뇨병, 뇌졸중, 바이러스감염, 세균감염등다양한질환과관련되어있다. 소포체는세포자멸사를유도하는다양한조절자들과상호연결되어있지만상세한분자적기전이나생리학적의의에대해서는아직도많은부분이알려져있지않다. 특히세균감염에대해서는바이러스감염에관한소포체스트레스의영향을연구한것에비교하여그다지많은연구가되어있지않다. 최근결핵균이나리스테리아와같은세포내기생세균뿐만아니라대장균과같은세균의감염과소포체스트레스반응에관련한연구결과들을보면소포체스트레스반응의조절기전이세균과숙주와의상호작용에서중요한역할을수행할것으로생각한다. 따라서소포체스트레스반응에서역할을담당하는다양한유전자나유전자의산물들과다른세포소기관들의분자들과의상호작용에관한연구가종합적으로이루어진다면아직까지알려지지않은세포의죽음과생존과같은생명현상을이해하는데많은도움을줄것으로기대한다.

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2016 학년도약학대학면접문제해설 문제 2 아래의질문에 3-4분이내로답하시오. 표피성장인자수용체 (epidermal growth factor receptor, EGFR) 는수용체티로신인산화효소군 (receptor tyrosine kinases, RTKs) 의일종으로서세

2016 학년도약학대학면접문제해설 문제 2 아래의질문에 3-4분이내로답하시오. 표피성장인자수용체 (epidermal growth factor receptor, EGFR) 는수용체티로신인산화효소군 (receptor tyrosine kinases, RTKs) 의일종으로서세 본문제에대한지적소유권은동국대학교에있습니다. 본교의서면허락없이무단으로출판, 게재, 사용할수없습니다. 문제 2 2016 학년도약학대학면접문제 아래의질문에 3-4 분이내로답하시오. 표피성장인자수용체 (epidermal growth factor receptor, EGFR) 는수용체티로신 인산화효소군 (receptor tyrosine kinases, RTKs) 의일종으로서세포의생존과증식