TY - JOUR
T1 - Requirement of FADD, NEMO, and BAX/BAK for aberrant mitochondrial function in tumor necrosis factor alpha-induced necrosis
AU - Irrinki, Krishna M.
AU - Mallilankaraman, Karthik
AU - Thapa, Roshan J.
AU - Chandramoorthy, Harish C.
AU - Smith, Frank J.
AU - Jog, Neelakshi R.
AU - Gandhirajan, Rajesh Kumar
AU - Kelsen, Steven G.
AU - Houser, Steven R.
AU - May, Michael J.
AU - Balachandran, Siddharth
AU - Madesh, Muniswamy
N1 - Irrinki, Krishna M Mallilankaraman, Karthik Thapa, Roshan J Chandramoorthy, Harish C Smith, Frank J Jog, Neelakshi R Gandhirajan, Rajesh Kumar Kelsen, Steven G Houser, Steven R May, Michael J Balachandran, Siddharth Madesh, Muniswamy eng HL086699-01A2S1/HL/NHLBI NIH HHS/ R01 HL096642/HL/NHLBI NIH HHS/ 1S10RR027327-01/RR/NCRR NIH HHS/ S10 RR027327/RR/NCRR NIH HHS/ R01 HL086699/HL/NHLBI NIH HHS/ T32 CA009035/CA/NCI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Mol Cell Biol. 2011 Sep;31(18):3745-58. doi: 10.1128/MCB.05303-11. Epub 2011 Jul 11.
PY - 2011/9
Y1 - 2011/9
N2 - 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-α)-induced necroptosis requires the adaptor proteins FADD and NEMO. FADD was found to mediate formation of the TNF-α-induced pronecrotic RIP1-RIP3 kinase complex, whereas the IκB Kinase (IKK) subunit NEMO appears to function downstream of RIP1-RIP3. Interestingly, loss of RelA potentiated TNF-α-dependent necroptosis, indicating that NEMO regulates necroptosis independently of NF-κB. 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.
AB - 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-α)-induced necroptosis requires the adaptor proteins FADD and NEMO. FADD was found to mediate formation of the TNF-α-induced pronecrotic RIP1-RIP3 kinase complex, whereas the IκB Kinase (IKK) subunit NEMO appears to function downstream of RIP1-RIP3. Interestingly, loss of RelA potentiated TNF-α-dependent necroptosis, indicating that NEMO regulates necroptosis independently of NF-κB. 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.
KW - Animals
KW - Apoptosis/physiology
KW - Blotting, Western
KW - Fas-Associated Death Domain Protein/metabolism
KW - Flow Cytometry
KW - GTPase-Activating Proteins/metabolism
KW - Gene Knockout Techniques
KW - Immunoprecipitation
KW - Intracellular Signaling Peptides and Proteins/metabolism
KW - Membrane Potential, Mitochondrial
KW - Mice
KW - Mitochondria/metabolism
KW - NF-kappa B/metabolism
KW - Necrosis/metabolism
KW - Reactive Oxygen Species
KW - Receptor-Interacting Protein Serine-Threonine Kinases/metabolism
KW - Signal Transduction
KW - Transcription Factor RelA/antagonists & inhibitors
KW - Tumor Necrosis Factor-alpha/metabolism
KW - bcl-2 Homologous Antagonist-Killer Protein/deficiency
KW - bcl-2-Associated X Protein/deficiency
UR - http://www.scopus.com/inward/record.url?scp=80052583012&partnerID=8YFLogxK
U2 - 10.1128/MCB.05303-11
DO - 10.1128/MCB.05303-11
M3 - Article
C2 - 21746883
SN - 0270-7306
VL - 31
SP - 3745
EP - 3758
JO - Molecular and Cellular Biology
JF - Molecular and Cellular Biology
IS - 18
ER -