S-nitrosylation of FLICE inhibitory protein determines its interaction with RIP1 and activation of NF-kappa B

Details

• Personal Author:
  Azad N ; Iyer AKV ; Luanpitpong S ; Rojanasakul Y ; Stehlik C ; Talbott SJ ; Wang LY
• Description:
  Death receptor (DR) ligation can lead to divergent signaling pathways causing either caspase-mediated cell death or cell proliferation and inflammation. These variations in cellular fate are determined by adaptor proteins that are recruited to the DR signaling complex. FLICE inhibitory protein (FLIP) is an established inhibitor of caspase-8-mediated apoptosis, and it is also involved in NF-kappa B activation. However, the molecular mechanism that regulates FLIP within this complex is unknown. In this study, we provide new evidence for the regulation of NF-kappa B by FLIP through S-nitrosylation, which involves covalent modification of the protein's cysteine thiol by nitric oxide to form S-nitrosothiol. Point mutations of FLIP at cysteine residues 254 and 259 prevent FLIP S-nitrosylation and its ability to activate NF-kappa B. The mechanism by which FLIP nitrosylation regulates NF-kappa B activity involves RIP1 binding and redistribution, whereas TRAF2 binding and distribution are unaffected. We further show that FLIP processing and cleavage is dependent on its nitrosylation status. Collectively, our study reveals a novel pathway for FLIP regulation of NF-kappa B through protein S-nitrosylation, which is a key posttranslational mechanism controlling DR-mediated cell death and survival. Since increased expression of FLIP and nitric oxide are frequently observed in chemotherapy-resistant tumors, S-nitrosylation of FLIP could be a key mechanism of chemoresistance and tumor growth. [Description provided by NIOSH]
• Subjects:
  Occupational Health Safety
• Keywords:
  Cell-biology Cell-damage Cell-function Cell-metabolism Cellular-function Cellular-reactions Molecular-biology Molecular-structure Proteins
• ISSN:
  1538-4101
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  OSHA Region 3 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  13
• Issue:
  12
• NIOSHTIC Number:
  nn:20044754
• Citation:
  Cell Cycle 2014 Jun; 13(12):1948-1957
• Contact Point Address:
  Yon Rojanasakul, West Virginia University, Department of Pharmaceutical Science, Morgantown, WV 26506
• Email:
  yrojan@hsc.wvu.edu
• CAS Registry Number:
  Nitric acid (CAS RN 7697-37-2)
• Federal Fiscal Year:
  2014
• Peer Reviewed:
  True
• Source Full Name:
  Cell Cycle
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:761fe059fabcd7105c9b34ee2d82beda75b27db61293a5b5bd42b2c855f104f7634c46f15eaa0c321cdc647ce4f97599aef7e7cee8b2300f0db7b428cc596f09
• Download URL:
  https://stacks.cdc.gov/view/cdc/200390/cdc_200390_DS1.pdf
• File Type:
  [PDF - 3.02 MB ]