Requirement of FADD, NEMO, and BAX/BAK for Aberrant Mitochondrial Function in Tumor Necrosis Factor Alpha-Induced Necrosis

被引:91
作者
Irrinki, Krishna M. [1 ]
Mallilankaraman, Karthik [1 ]
Thapa, Roshan J. [2 ]
Chandramoorthy, Harish C. [1 ]
Smith, Frank J. [1 ]
Jog, Neelakshi R. [3 ]
Gandhirajan, Rajesh Kumar [1 ]
Kelsen, Steven G. [3 ]
Houser, Steven R. [4 ]
May, Michael J. [5 ]
Balachandran, Siddharth [2 ]
Madesh, Muniswamy [1 ]
机构
[1] Temple Univ, Dept Biochem, Philadelphia, PA 19140 USA
[2] Fox Chase Canc Ctr, Immune Cell Dev & Host Def Program, Philadelphia, PA 19111 USA
[3] Temple Univ, Dept Med, Philadelphia, PA 19140 USA
[4] Temple Univ, Dept Physiol, Philadelphia, PA 19140 USA
[5] Temple Univ, Dept Anim Biol, Sch Vet Med, Philadelphia, PA 19140 USA
基金
美国国家卫生研究院;
关键词
NF-KAPPA-B; NECROTIC CELL-DEATH; SUPEROXIDE-DISMUTASE GENE; BCL-2; FAMILY-MEMBERS; DOMAIN KINASE RIP; PERMEABILITY TRANSITION; INTERACTING PROTEIN; CYCLOPHILIN-D; REACTIVE OXYGEN; CYTOCHROME-C;
D O I
10.1128/MCB.05303-11
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Necroptosis represents a form of alternative programmed cell death that is dependent on the kinase RIP1. RIP1-dependent necroptotic death manifests as increased reactive oxygen species (ROS) production in mitochondria and is accompanied by loss of ATP biogenesis and eventual dissipation of mitochondrial membrane potential. Here, we show that tumor necrosis factor alpha (TNF-alpha)-induced necroptosis requires the adaptor proteins FADD and NEMO. FADD was found to mediate formation of the TNF-alpha-induced pronecrotic RIP1-RIP3 kinase complex, whereas the I kappa B Kinase (IKK) subunit NEMO appears to function downstream of RIP1-RIP3. Interestingly, loss of RelA potentiated TNF-alpha-dependent necroptosis, indicating that NEMO regulates necroptosis independently of NF-kappa B. Using both pharmacologic and genetic approaches, we demonstrate that the overexpression of antioxidants alleviates ROS elevation and necroptosis. Finally, elimination of BAX and BAK or overexpression of Bcl-x(L) protects cells from necroptosis at a later step. These findings provide evidence that mitochondria play an amplifying role in inflammation-induced necroptosis.
引用
收藏
页码:3745 / 3758
页数:14
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