Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 115, Issue 9, Pages E2001-E2009Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1722013115
Keywords
RIPK1; death domain; dimerization; necroptosis; RIPK1-dependent apoptosis
Categories
Funding
- China National Natural Science Foundation [31530041]
- National Key R&D Program of China [2016YFA0501900]
- Chinese Academy of Sciences
- National Institute of Neurological Disorders and Stroke [1R01NS082257]
- National Institute on Aging [1R01AG047231, RF1AG055521]
- Natural Science Foundation of Shanghai [16ZR1443900]
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS082257] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [R01AG047231, RF1AG055521] Funding Source: NIH RePORTER
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RIPK1 is a critical mediator of cell death and inflammation downstream of TNFR1 upon stimulation by TNF alpha, a potent proinflammatory cytokine involved in a multitude of human inflammatory and degenerative diseases. RIPK1 contains an N-terminal kinase domain, an intermediate domain, and a C-terminal death domain (DD). The kinase activity of RIPK1 promotes cell death and inflammation. Here, we investigated the involvement of RIPK1-DD in the regulation of RIPK1 kinase activity. We show that a charge-conserved mutation of a lysine located on the surface of DD (K599R in human RIPK1 or K584R in murine RIPK1) blocks RIPK1 activation in necroptosis and RIPK1-dependent apoptosis and the formation of complex II. Ripk1(K584R/K584R) knockin mutant cells are resistant to RIPK1 kinase-dependent apoptosis and necroptosis. The resistance of K584R cells, however, can be overcome by forced dimerization of RIPK1. Finally, we show that the K584R RIPK1 knockin mutation protects mice against TNF alpha-induced systematic inflammatory response syndrome. Our study demonstrates the role of RIPK1-DD in mediating RIPK1 dimerization and activation of its kinase activity during necroptosis and RIPK1-dependent apoptosis.
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