Cell death by programmed necrosis is distinct from apoptosis in morphology and mechanism. Necrotic cells rapidly lose their plasma membrane integrity. The release of endogenous """"""""danger signals"""""""" trigger inflammation and can impact the quality and magnitude of innate and adaptive immune responses. Mechanistically, programmed necrosis is optimally induced when caspases are inhibited, such as that during infections with viruses that encode caspase inhibitors. A role for programmed necrosis is bolstered by the identification of viral inhibitors against programmed necrosis, such as certain viral FLIPs (FLICE(caspase-8)-like inhibitor proteins) and the mouse cytomegalovirus (MCMV) M45 protein. Despite the importance of programmed necrosis in inflammation and anti-viral immunity, the molecular pathway that regulates programmed necrosis is relatively undefined. We sought to understand the molecular regulation of programmed necrosis by screening a small interference RNA (siRNA) library of kinase genes. From our screen, we identified two members of the receptor interacting protein family, RIP1 and RIP3, as crucial regulators for TNF-induced programmed necrosis. In this application, we will examine the molecular mechanisms that regulate RIP1/RIP3-dependent programmed necrosis. Specifically, we will examine the role of protein phosphorylation and ubiquitination in regulating RIP1 and RIP3 activity. In addition, we will examine the mechanisms by which RIP1 and RIP3 activates the downstream effector phase of programmed necrosis. Specifically, we will examine how the pro-necrotic RIP1-RIP3 complex modulates the function of the mitochondria permeability transition pore (mPTP). Finally, we will evaluate the physiological relevance of RIP3-dependent programmed necrosis using vaccinia virus infection as a model. Specifically, we will examine how inhibition of programmed necrosis in RIP3-deficient mice affects virus-induced necrosis, inflammation, and subsequent adaptive immune responses.

Public Health Relevance

Cell death by necrosis causes inflammation and can greatly impact the quality of an immune response. In this proposal, we will study the molecular signals that control cell death by necrosis and evaluate how it impacts the efficiency of immune responses against virus infections. These studies will allow us to better understand the signals that control inflammation and to develop strategies to control it in physiological and pathological conditions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI083497-04
Application #
8442199
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Leitner, Wolfgang W
Project Start
2010-04-01
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
4
Fiscal Year
2013
Total Cost
$382,709
Indirect Cost
$150,059
Name
University of Massachusetts Medical School Worcester
Department
Pathology
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Moriwaki, Kenta; Chan, Francis Ka-Ming (2016) Necroptosis-independent signaling by the RIP kinases in inflammation. Cell Mol Life Sci 73:2325-34
Moriwaki, Kenta; Farias Luz, Nivea; Balaji, Sakthi et al. (2016) The Mitochondrial Phosphatase PGAM5 Is Dispensable for Necroptosis but Promotes Inflammasome Activation in Macrophages. J Immunol 196:407-15
Moriwaki, Kenta; Chan, Francis Ka-Ming (2016) Regulation of RIPK3- and RHIM-dependent Necroptosis by the Proteasome. J Biol Chem 291:5948-59
Farias Luz, Nivea; Balaji, Sakthi; Okuda, Kendi et al. (2016) RIPK1 and PGAM5 Control Leishmania Replication through Distinct Mechanisms. J Immunol 196:5056-63
Chan, Francis Ka-Ming; Luz, Nivea Farias; Moriwaki, Kenta (2015) Programmed necrosis in the cross talk of cell death and inflammation. Annu Rev Immunol 33:79-106
Moriwaki, Kenta; Bertin, John; Gough, Peter J et al. (2015) A RIPK3-caspase 8 complex mediates atypical pro-IL-1β processing. J Immunol 194:1938-44
Moriwaki, K; Bertin, J; Gough, P J et al. (2015) Differential roles of RIPK1 and RIPK3 in TNF-induced necroptosis and chemotherapeutic agent-induced cell death. Cell Death Dis 6:e1636
Upton, Jason W; Chan, Francis Ka-Ming (2014) Staying alive: cell death in antiviral immunity. Mol Cell 54:273-80
Zhang, Jianke; Chan, Francis Ka-Ming (2014) Cell biology. RIPK3 takes another deadly turn. Science 343:1322-3
Mandal, Pratyusha; Berger, Scott B; Pillay, Sirika et al. (2014) RIP3 induces apoptosis independent of pronecrotic kinase activity. Mol Cell 56:481-95

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