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1 학술원논문집 ( 자연과학편 ) 제 52 집 2 호 (2013) 세포사멸기전 : 예정세포사, 세포괴사및예정세포괴사 최상돈 * 권혁권 ** 신현준 ** 1) The Mechanisms of Cell Death: Apoptosis, Necrosis and Necroptosis Sangdun Choi* Hyuk-Kwon Kwon* Hyeon-Jun Shin* ABSTRACT The deregulation of cell death can cause a variety of diseases such as neurodegeneration, autoimmunity, cancer and developmental disorders. Therefore, to elucidate its mechanism is of crucial importance. To study cell death mechanisms began when the apoptosis was discovered in Before this, all the cell deaths were considered as the result of detrimental and fatal changes, which cannot be regulated. However, the induction of necrosis by tumor necrosis factor (TNF) was unveiled in 1988 that uncovered the regulatory mechanisms of the necrosis, which resulted in a new concept known as programmed necrosis or necroptosis. This new phenomenon, necroptosis, received a great attention and a number of studies have been performed to elucidate the detailed mechanism. In this * 아주大學校分子科學技術學科敎授 ** 아주大學校分子科學技術學科博士課程접수일 2013 년 11 월 25 일

2 2 최상돈 권혁권 신현준 review, we will try to cover the historical background and the mechanisms involved in programmed cell death (apoptosis), necrosis, and programmed necrosis (necroptosis). We will also highlight the recent research trends in this field and the outcome of the cell death researches. Key words : apoptosis, cell death, necroptosis, necrosis 초 록 세포사멸조절의이상은암, 신경퇴화, 면역질환이나발생장애등다양한질병을유발할수있기때문에생물학자들에게있어세포사멸기전연구는매우중요하다. 세포사멸연구의역사는 1972년예정세포사 (apoptosis) 의발견으로부터시작된다. 이전의세포사멸은모두세포괴사 (necrosis) 로여겨졌으며조절할수없는것이라믿어졌다. 하지만 1988년 TNF(tumor necrosis factor) 에의한세포괴사유도가보고되고이의조절기전들이밝혀지면서예정세포괴사 (programmed necrosis 또는 necroptosis) 개념이형성되었다. 현재예정세포괴사는세포사멸연구분야중큰주목을받고있으며그기전을밝히기위해많은연구가진행되고있다. 본리뷰에서는기존에보고된내용을바탕으로세포사멸연구의발달과정과예정세포사, 세포괴사, 예정세포괴사의세포사멸기전을소개하고, 최근의연구동향, 연구가치및미래의기대효과에대하여논의하고자한다. 주제어 : 예정세포사, 세포사멸, 예정세포괴사, 세포괴사 Ⅰ. 서론 Ⅱ. APOPTOSIS ( 예정세포사 ) Ⅲ. NECROSIS ( 세포괴사 ) 차 례 Ⅳ. NECROPTOSIS ( 예정세포괴사 ) Ⅴ. 결론참고문헌 Ⅰ. 서론 인간은다양한자극과스트레스에노출되어있으며이에의해여러가지건강상의문제와질병이야기된다. 특정요인에의해손상또는신호를받은세포및세포내소

3 세포사멸기전 : 예정세포사, 세포괴사및예정세포괴사 3 기관은분자적메커니즘에의해세포사멸이유도되는데, 이는우리몸을보호하거나발생학적으로전개시키기도하지만각종병리학적문제를유발시킬수있기때문에이에대한연구는생명과학에있어매우중요하다. 1970년대초반, Kerr와그의동료들은핵과세포질의응축및파손을보이는특이한형태의동물세포사멸을발견하고이를 apoptosis( 예정세포사 ) 라고명명하였으며 (Kerr et al. 1972), 이후 Caenorhabditis elegans( 예쁜꼬마선충 ) 를통한연구로 apoptosis의정형화된특징들이제안되었고세포사멸과정이조절될수있다고여겨지게되었다 (Lettre and Hengartner 2006). 한편, 1973년 Schweichel과 Merker는세포사멸을형태학적으로분류하였는데, type I 세포사멸은 heterophagy, type II 세포사멸은 autophagy 와연관성이있고, type III 세포사멸은소화과정이없는사멸이라고정의하였다 (Schweichel and Merker 1973). 현재 type I 세포사멸을 apoptosis, type II 세포사멸을 autophagy( 자가소화작용 ), type III 세포사멸은 necrosis( 세포괴사 ) 라고구분하고있다 (Kroemer et al. 2009). Necrosis는감염, 독소, 외상등에의해세포사멸이발생하는과정으로특별히조절되지않는기전으로알려져왔으나, 1988년 tumor necrosis factor(tnf) 에의해 necrosis가유도될수있다는발견은 apoptosis 연구에몰두했던생물학자들에게새로운과제를던져놓았다 (Laster et al. 1988). 돌연세포사로여겨지던 necrosis가예정사 (programmed death) 할수있다는증거들이계속등장하면서 2003년 Chan은 programmed necrosis 라는개념을소개하여조절가능한세포사멸의범주에 necrosis 를포함시켰으며 (Chan et al. 2003), 곧이어 apoptosis처럼조절가능한 necrosis라는의미의 necroptosis( 예정세포괴사 ) 라는개념이생겨나게되었다 (Degterev et al. 2005). Ⅱ. APOPTOSIS ( 예정세포사 ) Apoptosis는 1972년 Kerr와그의동료들에의해형태학적으로알려졌으며 (Kerr et al. 1972), 일반적으로세포수축, 핵의응축및세포막기포형성이특징적이다. 세포수축은세포골격의손상에의한세포크기감소, 세포질응집및세포내소기관들의밀집을의미한다. 핵응축은단백질분해효소와핵산분해효소에의한핵파괴및염색

4 4 최상돈 권혁권 신현준 질 (chromatin) 이응축되는일련의과정을말하며, apoptosis 가진행되는세포는세포막에기포가발생하고전체적으로 apoptotic body( 예정세포사체 ) 라불리는소체를형성한다. Apoptosis 에조절장애가생겨이상세포가축적하면암등의질환으로, 또는지나친세포손실의경우뇌졸증, 심장마비, 신경퇴화등의질환을일으키는것으로알려져있다 (Reed 2000). Apoptosis를유발하는경로는내인성경로와외인성경로로구분된다. 내인성경로는 DNA 손상, 사이토카인, 활성산소종 (reactive oxygen species; ROS) 등의자극에의해유발되며이런자극은 mitochondrial permeability transition pore( 미토콘드리아투과도전이미세공 ) 를열리게함으로써미토콘드리아막의전위조절능력을파괴하면서 cytochrome c, second mitochondria-derived activator of caspases(smac; direct IAP binding protein with low pi [DIABLO] 라고도함 ), high temperature requirement protein A2(HtrA2; Omi라고도함 ) 와같은 apoptosis 개시단백질들을세포질로유출시킨다 (Du et al. 2000; Saelens et al. 2004; Garrido et al. 2006). Cytochrome c는 apoptotic protease activating factor 1(APAF1) 및 caspase-9과결합하여 apoptosome 을형성한후 caspase-3를활성화시켜세포사멸을유도한다 (Hill et al. 2004). 외인성경로는 FAS(TNF receptor superfamily member 6) receptor(fasr), tumor necrosis factor receptor 1(TNFR1) 및 tumor necrosis factor receptor superfamily member 25(TNFRSF25; DR3), 10A(TNFRSF10A; DR4), 10B (TNFRSF10B; DR5) 와같은 death receptor에의해개시된후 Fas-associated protein with death domain(fadd) 또는 TNFRSF1A-associated via death domain(tradd) adaptor와결합하여 apoptosis 신호를세포내로전달한다. 전달된신호는 death-inducing signaling complex(disc) 와 apoptosis 관련시스테인펩티다제인 caspase-8/caspase-3 경로를통해세포사멸을유도한다 (Kischkel et al. 1995). 이외에도세포독성 T세포에의해생성된 perforin/granzyme에의한세포사멸도보고되었다 (Trapani and Smyth 2002; Goping et al. 2003). 활성화된세포독성 T 세포는 perforin을만들어세포막에구멍을뚫고안쪽으로 granzyme을유입시킨다. 유입된 granzyme은 caspase-10을이용하거나직접 caspase-3를활성화시켜여러가지단백질을분해함으로써세포사멸을진행한다. 이처럼 apoptosis는다양한자극에의해유발되고조직적인신호전달경로를통하여조절된다

5 세포사멸기전 : 예정세포사, 세포괴사및예정세포괴사 5 Ⅲ. NECROSIS ( 세포괴사 ) Necrosis는 apoptosis와는달리조직적으로조절되지않는세포사고사또는돌연사로간주되었으며, 세포괴사가진행중인세포는초기에세포막이파괴되고삼투압의불균형에따른세포외부로부터의수분유입에의해세포전체및미토콘드리아와핵의손상이 apoptosis와는뚜렷이구별되는형태학적변화를나타내고있다 (Edinger and Thompson 2004; Kroemer et al. 2005). 또한 necrosis는세포가파괴되면서빠져나온손상된세포내소기관들에의해국소적염증반응을일으키기때문에염증반응과연관성이깊은선천면역계 (innate immune system) 에서특히중요한역할을하고있다 (Savill and Fadok 2000; Zitvogel and Kroemer 2008). 1988년 Laster와그의동료들에의해 TNF가세포주에따라 apoptosis와 necrosis 모두를유도할수있다는발견은기존의형태학적특징만으로구분지어졌던 necrosis 의전환점이되었다 (Laster et al. 1988; Vandenabeele et al. 2010). 1992년 TNF가유도하는세포독성에서미토콘드리아에서생성된산소라디칼이주된요인임을보고하였으며 (Schulze-Osthoff et al. 1992), 글루타민의산화적대사과정이 necrosis와연관성이있다는연구 (Goossens et al. 1996), 산화적스트레스가 apoptosis나 necrosis의원인이라는연구 (Tan et al. 1998; Choi et al. 2009) 및쥐의섬유아세포 L929에서 caspase 억제에의해 TNF 매개 necrosis가증가한다는결과 (Vercammen et al. 1998) 등이발표되었다. 이와같이지속적인연구가진행되면서 necrosis는전부비조절적세포사멸이라는과거의인식에서벗어나 apoptosis처럼분자적메커니즘에의해조절될수있는부분이있다는것을인정하면서, 이를 programmed necrosis 또는 necroptosis 영역으로구분하기시작하였다. Ⅳ. NECROPTOSIS ( 예정세포괴사 ) 1. Necroptosis 의역사 1988 년 TNF 에의해 necrosis 가체계적으로유도된다는보고가있었다 (Laster et

6 6 최상돈 권혁권 신현준 al. 1988). 이후 TNF나 TNF-related apoptosis-inducing ligand(trail) 에의한 necrosis에서 receptor-interacting protein(rip) 이필요하다는사실을밝혀냈고 (Holler et al. 2000), TNFR과 RIP을통한 necrosis 유도연구를통해 necrosis가잘통제되고있다는의미에서 programmed necrosis 란용어가제안되었다 (Chan et al. 2003). 이전의 programmed cell death는 apoptosis의전유물로생각하였으나 necrosis 도조절된세포사멸이며이와관련된메커니즘의중요성이본격적으로논의되기시작한것이다. 2004년에는 DNA 손상에의해서도 necrosis가유도될수있음이보고되었고 (Zong et al. 2004), 2005년에는 necrostatin-1 단백질의발견과함께이제는 necrosis의형태학적특징이보이면서절도있게자가포식이활성화되는현상을 necroptosis 라고처음으로명명하였다 (Degterev et al. 2005). 2006년에는 adenosine diphosphate(adp) 와 adenosine triphosphate(atp) 를교환해주는효소인 adenine nucleotide translocase가억제되면 RIP을매개로하는 necroptosis가유도된다는보고가있었고 (Temkin et al. 2006), 이어 necroptosis를시스템생물학적인방법으로접근하여기존의 apoptosis와는다른분자적신호전달경로및관련유전체에대한연구결과가발표되었다 (Hitomi et al. 2008). 또한 necrostatin-1이 RIP1에특이적으로결합하여 RIP1의활성을억제한다는것이발표되었고 (Degterev et al. 2008), RIP1/RIP3 의결합및 RIP3에의한 necroptosis 과정이발표되기도하였다 (Cho et al. 2009; He et al. 2009; Zhang et al. 2009). RIP1/3 외의다양한 necroptosis 조절요인들, 예를들면 caspase 억제제 (Vercammen et al. 1998), ubiquitin E3 ligases와 deubiquitylating 효소 (Hitomi et al. 2008; He et al. 2009), 미토콘드리아나 NADPH oxidase 1(NOX1) 에의해생성된 ROS(Goossens et al. 1999b; Kim et al. 2007; Yazdanpanah et al. 2009), B cell lymphoma 2(BCL-2) 계열 (Hitomi et al. 2008), poly(adp-ribose) polymerase 1(PARP-1) (Zong et al. 2004) 등에대한분자적기전이보고되었다. 최근에는 RIP1/3에의한 necrosome 형성및 PARP-1, JNK(c-Jun N-terminal kinase), calpain, cathepsin, AIF(apoptosis-inducing factor) 등이관여하는 necroptosis 역시보고되었으며 (Li et al. 2012; Sosna et al. 2013), DNA 손상에의해유도된 necroptosis가 PARP-1/AIF 신호전달경로를통하여진행된다는발견도있었다 (Baritaud et al. 2012; Cabon et al. 2012). 면역세포의 Toll-like receptor(tlr) 신호전달경로에의해활성화된 RIP, cathepsin D, JNK, ROS를통한 necroptosis도등

7 세포사멸기전 : 예정세포사, 세포괴사및예정세포괴사 7 장하였다 (Kim and Li 2013; Zou et al. 2013). 이와같이 necroptosis는지속적으로연구가거듭되어오면서이제는분자적메커니즘에의해잘조절되고있는 necrosis를종합적으로지칭하는하나의큰개념이되었다. 2. Necroptosis 신호경로 ( 그림 1 참조 ) 1) TNF에의한 necroptosis RIP 단백질은 TNF가유도하는 necrosome 형성에있어가장핵심적인분자이다. RIP1은 TNFR 신호경로에서처음발견되었으며 nuclear factor kappa-light-chainenhancer of activated B cells (NF-κB) 신호경로와 necroptosis에서다양한기능을하는것으로알려져있다 (Hsu et al. 1996a). RIP3도 apoptosis와 NF-κB 활성화연구에서처음으로보고되었고 (Yu et al. 1999), 새로운 apoptosis 유도 kinase로서의기능도밝혀졌다 (Sun et al. 1999). 최근에는 necroptosis가일어나는과정에서 necrosome 형성을위해 RIP1과 RIP3 복합체형성이선행되어야한다는발표가있었다 (Li et al. 2012). 이외에도 necrosome과상호작용하여직간접적으로영향을미치는분자로 TRADD, TNF receptor-associated factor 2(TRAF2), FADD 등도제시되었다. 예를들면, TRADD는 TNFR1과함께세포사멸과 NF-κB 활성을유도하며 (Hsu et al. 1995), TRAF2와결합하거나 FADD와상호작용하여각기다른신호전달경로를유도하는것으로알려져있다 (Hsu et al. 1996b). TNF에의한 necroptosis 경로는어떤복합체를형성하느냐에따라크게두가지로나뉜다. 첫째, TNF 리간드가 TNFR1과결합하여 TRADD, RIP1, cellular inhibitor of apoptosis protein (ciap), TRAF2, TRAF5 등과 TNFR complex I 복합체를형성하면 ciap에의해 RIP1의 Lys63 ubiquitylation이유도되고, 이로인해 transforming growth factor-β activated kinase 1 (TAK1), TAK1-binding protein 2 (TAB2), TAB3 복합체가형성되어 NF-κB 활성화경로를개시한다. 활성화된 NF-κB는핵내로이동하여면역, 염증반응, 세포사멸, 세포생존, 세포분화와관련된각종전사인자및신호단백질들을발현시킨다. 이때 riboflavin kinase(rfk) 단백질은 TNFR1과 p22phox를구조적으로연결시킴으로써 ROS 생성을촉진하여 TNF가유도하는 necroptosis를유발시키게된다. 두번째는, TRADD, FADD, caspase-8, RIP1, RIP3가복합체를이루어 complex II를구성하는경우이다. Complex II는

8 8 최상돈 권혁권 신현준 caspase-8 활성유무에따라각기다른신호를전달하게되는데, caspase-8이활성화되면 RIP1과 RIP3를억제하여 caspase 의존적 apoptosis를유도하지만, caspase-8 활성이차단되면 RIP1과 RIP3는인산화에의해 necrosome을형성한후 necroptosis를유도한다 (Vandenabeele et al. 2010). 2) DNA 손상에의한 necroptosis DNA 손상이란 DNA 나선구조의파괴, DNA에서의염기실종, 비정상적염기로의치환등과같은 DNA의화학적또는구조적변화를의미한다. DNA 손상은대사과정에서발생한 ROS, reactive nitrogen species(rns), 지질과산화산물들과알킬화제들에의해유발될수있으며, 가수분해과정또한 DNA의화학결합을절단함으로써 DNA를손상시킬수있다 (De Bont and van Larebeke 2004). 이중 ROS에의한 DNA 손상이비교적잘알려져있는데, ROS는화학적반응성이있는산소포함분자 ( 과산화수소, 수퍼옥사이드라디칼, 히드록실라디칼 ) 들의총칭이며 manganese superoxide dismutase와 glutathione peroxidase 등의효소에의해분해된다. 하지만많은양의 ROS와분해효소들의감소에의해불가피하게증가된 ROS는 DNA 손상, 미토콘드리아의기능장애, 산화적스트레스를초래하여 apoptosis뿐만아니라 necroptosis를유발한다 (Devasagayam et al. 2004; Murphy 2009). L929나 mouse embryonic fibroblast(mef) 세포에서 TNF 자극에의해 ROS가발생한다는보고가있다 (Goossens et al. 1999a; Lin et al. 2004). DNA 손상에의해유발되는세포사멸의가장핵심적인분자로 PARP가잘알려져있다 (Zong et al. 2004). PARP-1과 PARP-2를포함한 PARP family는 ATP로부터유래한 β-nad + (β-nicotinamide adenine dinucleotide) 를기질로하여 ADP-ribose 중합체를합성하거나글루타민산, 아스파르트산등에 poly(adp-ribose) (PAR) 를붙이는효소이다 (Chambon et al. 1963). PARP는 DNA 단일가닥손상을인지하고 DNA 수선을위한단백질들을유도한다 (Schreiber et al. 2006). PARP가과활성화되거나과발현되면 ATP의과다한소모로인해 necrosis( 현재의 necroptosis) 를유발할수있다는연구도보고되었다 (Los et al. 2002). 알킬화에의한 DNA 손상은 PARP-1을활성화시키는데, 이는 NAD의손실과 PAR의축적을일으켜 AIF를미토콘드리아의막사이공간으로부터세포질로방출시키며이과정은 calpain(ca 2+ 에의해활성화되는 non-caspase Cys protease) 의존적으로일어난다 (Yu et al. 2002;

9 세포사멸기전 : 예정세포사, 세포괴사및예정세포괴사 9 Cao et al. 2007; Moubarak et al. 2007). 세포질로빠져나온 AIF는빠르게핵으로이동하여비교적큰규모로 DNA를절단하고 (Kroemer et al. 2007), 절단된 DNA로인해다시 PARP 활성화가이뤄지는악순환이반복된다. 이와관련하여최근에는알킬화에의해 DNA 손상을일으키는약물인 MNNG(N-methyl-N -nitro-n - nitrosoguanidine) 가유발하는 necroptosis에서, PARP-1 의과활성화를통해세포질로방출된 AIF가 caspase 비의존적으로작용한다는연구가보고되었다 (Cabon et al. 2012). 이보고에따르면 MNNG에의한 DNA 손상이 PARP를활성화시키고 PARP로인해 NAD와 ATP가손실되면서 PAR 중합체가핵내에축적된다. PAR 의축적은 calpain 활성화에기여하고 calpain은미토콘드리아내로들어가 AIF를이동할수있도록잘라주거나 BID를 truncated Bid(tBID) 로만들어활성화시킨다. 활성화된 BID는 BAX로하여금미토콘드리아로부터 AIF가빠져나올수있도록통로를만들게한다. 최근보고에따르면, 미토콘드리아의기능장애로인해발생한 ROS가 DNA 손상과함께 PARP-1의과발현을유도하고 ATP 손실을불러와 5' AMP-activated protein kinase(ampk) 를활성화시키며, 이는 autophagosome 형성을억제하는 mammalian target of rapamycin complex 1(mTORC1) 을억제함으로써결과적으로 autophagy에의한세포사멸을유도하고있다 (Rodriguez-Vargas et al. 2012). 3) Toll-like receptor 를통한 necroptosis TLR 은선천면역의핵심역할을하는수용체로서, TLR 신호경로는 lipopolysaccharide(lps), 세균의메틸화되지않은 CpG DNA, 바이러스 RNA 등다양한병원성성분들을인식하여 NF-κB 를활성화시킴으로써염증성사이토카인들을유도한다. 하지만과도한 TLR의활성화는자가면역질환이나염증성질환으로이어지는세포사멸을초래하기도한다 (Huang et al. 2011). Polyinosinic-polycytidylic acid[poly(i:c)] 의자극에의해 TLR3/TRIF(TIRdomain-containing adapter-inducing interferon-β) 를매개로유도된 NF-κB 활성이 RIP1에의존적이라고확인되었으며 (Meylan et al. 2004), poly(i:c)/rig-i-like receptor(retinoic acid-inducible gene 1-like receptor) 의신호를통하여세포질로유출된 cathepsin D와 mitochondrial adaptor IPS-1(IFN-β promoter stimulator 1) 의결합에의해수지상세포의 necroptosis가유도된다는보고도있었다 (Morato et al

10 10 최상돈 권혁권 신현준 2010). LPS/TLR4/TRIF의신호전달은 RIP1 의존적으로 NF-κB 활성을유도하거나, RIP1 비의존적으로 IRF3의활성을조절하기도한다 (Press et al. 2012). TLR3와 TLR4의경우직접적인 RIP1/RHIM(RIP homotypic interaction motif)/rip3의결합을통하여 necroptosis가유도됨이밝혀졌다 (Krishnan et al. 2012). Poly(I:C) 또는 LPS를 TLR3 또는 TRL4가인지하였을때발생한 TNF에비의존적으로 RIP3가 necrosis를매개한다는것이생쥐의대식세포에서발견되기도하였다 (He et al. 2011). 이보고에따르면, TLR adaptor 분자로알려진 TRIF/TICAM-1(TIR-domaincontaining adapter molecule-1) 은 TLR3/TLR4 활성화에의해 RIP3와결합하며이복합체는 TLR3/TLR4가유도하는 necrosis에서필수적인역할을수행한다. 한편 UV 투사에의해발생한 necroptosis는 TLR4 신호경로중 myeloid differentiation primary response 88(MyD88) 에의해매개된다는연구결과가최근보고되었다 (Harberts et al. 2013). 그림 1. Necroptotic signaling pathways

11 세포사멸기전 : 예정세포사, 세포괴사및예정세포괴사 11 Ⅴ. 결론 세포사멸에대해연구하는궁극적인목적은부적절한세포사멸로인해유발되는여러가지질병에대해효과적인치료방법을개발하는데있다. 실제로세포사멸중가장먼저알려진 apoptosis를표적으로하는물질들이임상에서환자들에게치료제로사용되고있다. 그중 rasagiline( 상품명 Azilect) 은미토콘드리아의외막에존재하면서미토콘드리아내로콜레스테롤을전달해주는 peripheral benzodiazepine receptor(pbr) 에결합하여 apoptosis를저지하고그로인해뇌세포의사멸을방지하는파킨슨병치료제로사용된다 (Green and Kroemer 2005; Oldfield et al. 2007). 이밖에 apoptosis 를억제해세포사멸을막는치료제로 FDA 승인을받은것들은 p53를표적으로하는 amifostine, ROS를표적으로하는 edaravone, 26S proteasome을표적으로하는 bortezomib 등이있다 (Green and Kroemer 2005). 이런약물들이개발될수있었던것은세포사멸연구를통해내인성 / 외인성경로와같은분자적메커니즘및주요표적분자들의기능을규명했기때문에가능한일이었다. 반면에 necroptosis와관련된임상적용은 TNF 억제를통한관절염완화정도에그치고있는실정이다 (U.S. Food and Drug Administration: Necroptosis 경로의중요단백질및기전을표적으로하는약물개발을통해관련질환들의치료가능성이크게기대되는시기이다. 사사 이논문은 2013년도정부 ( 미래창조과학부 ) 의재원으로한국연구재단의지원을받아수행된연구임 (2012R1A2A2A ). 參考文獻 Baritaud, M., Cabon, L., Delavallee, L., Galan-Malo, P., Gilles, M.E., Brunelle- Navas, M.N. and Susin, S.A AIF-mediated caspase-independent

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