2. Academic Validation
  3. Death-domain dimerization-mediated activation of RIPK1 controls necroptosis and RIPK1-dependent apoptosis

Death-domain dimerization-mediated activation of RIPK1 controls necroptosis and RIPK1-dependent apoptosis

  • Proc Natl Acad Sci U S A. 2018 Feb 27;115(9):E2001-E2009. doi: 10.1073/pnas.1722013115.
Huyan Meng 1 2,  Zhen Liu 1,  Xingyan Li 1 2,  Huibing Wang 1 2 3,  Taijie Jin 1 2,  Guowei Wu 1 2,  Bing Shan 1,  Dana E Christofferson 3,  Chunting Qi 4,  Qiang Yu 4,  Ying Li 5,  Junying Yuan 5 3
Affiliations

Affiliations

  • 1 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 201203 Shanghai, China.
  • 2 University of Chinese Academy of Sciences, 100049 Beijing, China.
  • 3 Department of Cell Biology, Harvard Medical School, Boston, MA 02115.
  • 4 Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203 Shanghai, China.
  • 5 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 201203 Shanghai, China; liying@sioc.ac.cn junying_yuan@hms.harvard.edu.
PMID: 29440439 DOI: 10.1073/pnas.1722013115
Abstract

RIPK1 is a critical mediator of cell death and inflammation downstream of TNFR1 upon stimulation by TNFα, 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. RIPK1K584R/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 TNFα-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.

Keywords

RIPK1; RIPK1-dependent apoptosis; death domain; dimerization; necroptosis.

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