TNF binding to its receptor TNFR1 triggers cell survival or cell death but the mechanisms that determine which of these two divergent responses is triggered remain to be fully elucidated. One cell death checkpoint is the activation of NF-kappaB transcription factors and subsequent induction of anti-apoptotic genes to inhibit the apoptosis pathway. Preliminary studies performed demonstrated the existence of another cell death checkpoint regulated by lysine 63-linked ubiquitination of RIP1. Ubiquitination of lysine 377 on RIP1 inhibits TNF-induced apoptosis first through an NF-kappaB-independent mechanism, and subsequently through an NF-kappaB- dependent mechanism. In contrast, in the absence of ubiquitination, RIP1 serves as a pro- apoptotic signaling molecule. Thus, RIP1 is a dual-function molecule that can be either pro-survival or pro-death depending on its ubiquitination state and thus serves as an NF- kappaB-independent cell death switch early in TNF signaling. This study proposes to examine how this cell death checkpoint may be regulated. (1) The mechanism by which ubiquitination of RIP1, or the lack of it, regulates the activation of caspases will be examined. (2) The contribution by RIP1-binding partners to this checkpoint will also be tested. (3) Animal models with genetic modifications in this novel cell death checkpoint will be developed to study the relevance of this checkpoint in immune function. Insights gained from these studies may lead to the development of pharmacological agents that can modulate this cell death checkpoint. Such agents may have therapeutic potential in inflammatory diseases where TNF plays a role.

Public Health Relevance

TNF is an immune system hormone that contributes to rheumatoid arthritis and Crohn's Disease. Our aim is to figure out how TNF controls the lifespan of cells so that we can potentially manipulate this for therapeutic purposes in these diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI052417-09
Application #
8197670
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Peyman, John A
Project Start
2002-06-01
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
9
Fiscal Year
2012
Total Cost
$415,317
Indirect Cost
$170,292
Name
Icahn School of Medicine at Mount Sinai
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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Ting, Adrian T; Bertrand, Mathieu J M (2016) More to Life than NF-κB in TNFR1 Signaling. Trends Immunol 37:535-45
Justus, Scott J; Ting, Adrian T (2015) Cloaked in ubiquitin, a killer hides in plain sight: the molecular regulation of RIPK1. Immunol Rev 266:145-60
O'Donnell, Marie Anne; Hase, Hidenori; Legarda, Diana et al. (2012) NEMO inhibits programmed necrosis in an NFýýB-independent manner by restraining RIP1. PLoS One 7:e41238
O'Donnell, Marie Anne; Ting, Adrian T (2012) NFýýB and ubiquitination: partners in disarming RIPK1-mediated cell death. Immunol Res 54:214-26
O'Donnell, Marie Anne; Ting, Adrian T (2011) RIP1 comes back to life as a cell death regulator in TNFR1 signaling. FEBS J 278:877-87
O'Donnell, Marie Anne; Perez-Jimenez, Eva; Oberst, Andrew et al. (2011) Caspase 8 inhibits programmed necrosis by processing CYLD. Nat Cell Biol 13:1437-42
O'Donnell, Marie Anne; Ting, Adrian T (2010) Chronicles of a death foretold: dual sequential cell death checkpoints in TNF signaling. Cell Cycle 9:1065-71
Legarda-Addison, D; Hase, H; O'Donnell, M A et al. (2009) NEMO/IKKgamma regulates an early NF-kappaB-independent cell-death checkpoint during TNF signaling. Cell Death Differ 16:1279-88
O'Donnell, Marie Anne; Legarda-Addison, Diana; Skountzos, Penelopi et al. (2007) Ubiquitination of RIP1 regulates an NF-kappaB-independent cell-death switch in TNF signaling. Curr Biol 17:418-24

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