RIP1 suppresses innate immune necrotic as well as apoptotic cell death during mammalian parturition.

Abstract

The pronecrotic kinase, receptor interacting protein (RIP1, also called RIPK1) mediates programmed necrosis and, together with its partner, RIP3 (RIPK3), drives midgestational death of caspase 8 (Casp8)-deficient embryos. RIP1 controls a second vital step in mammalian development immediately after birth, the mechanism of which remains unresolved. Rip1(-/-) mice display perinatal lethality, accompanied by gross immune system abnormalities. Here we show that RIP1 K45A (kinase dead) knockin mice develop normally into adulthood, indicating that development does not require RIP1 kinase activity. In the face of complete RIP1 deficiency, cells develop sensitivity to RIP3-mixed lineage kinase domain-like-mediated necroptosis as well as to Casp8-mediated apoptosis activated by diverse innate immune stimuli (e.g., TNF, IFN, double-stranded RNA). When either RIP3 or Casp8 is disrupted in combination with RIP1, the resulting double knockout mice exhibit slightly prolonged survival over RIP1-deficient animals. Surprisingly, triple knockout mice with combined RIP1, RIP3, and Casp8 deficiency develop into viable and fertile adults, with the capacity to produce normal levels of myeloid and lymphoid lineage cells. Despite the combined deficiency, these mice sustain a functional immune system that responds robustly to viral challenge. A single allele of Rip3 is tolerated in Rip1(-/-)Casp8(-/-)Rip3(+/-) mice, contrasting the need to eliminate both alleles of either Rip1 or Rip3 to rescue midgestational death of Casp8-deficient mice. These observations reveal a vital kinase-independent role for RIP1 in preventing pronecrotic as well as proapoptotic signaling events associated with life-threatening innate immune activation at the time of mammalian parturition.

• Authors: William J Kaiser, Lisa P Daley-Bauer, Roshan J Thapa, Pratyusha Mandal, Scott B Berger, Chunzi Huang, Aarthi Sundararajan, Hongyan Guo, Linda Roback, Samuel H Speck, John Bertin, Peter J Gough, Siddharth Balachandran, Edward S Mocarski
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 111 Issue 21 Pg. 7753-8 (May 27 2014) ISSN: 1091-6490 [Electronic] United States
• PMID: 24821786 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• DNA Primers
• GTPase-Activating Proteins
• Ralbp1 protein, mouse
• Receptor-Interacting Protein Serine-Threonine Kinases
• Ripk3 protein, mouse
• Casp8 protein, mouse
• Caspase 8

Topics

• Animals
• Apoptosis (immunology)
• Caspase 8 (immunology)
• DNA Primers (genetics)
• Enzyme-Linked Immunosorbent Assay
• Flow Cytometry
• GTPase-Activating Proteins (genetics, immunology, metabolism)
• Gene Knock-In Techniques
• Immunity, Innate (immunology)
• Immunoblotting
• Mice
• Mice, Knockout
• Necrosis (immunology)
• Parturition (immunology)
• Receptor-Interacting Protein Serine-Threonine Kinases (immunology)
• Signal Transduction (immunology)