114 | Nature | Vol 577 | 2 January 2020
Article
Discussion
Our study identified a dominantly inherited autoinflammatory disease
caused by impaired caspase-8 cleavage in RIPK1. This condition is dis-
tinct from the previously reported recessively inherited RIPK1-deficient
condition that is characterized by immune deficiency^19 ,^20. By contrast,
we show that patients with one copy of mutated RIPK1 in the caspase-8
cleavage site present with symptoms of immune dysfunction, including
recurrent fevers and lymphadenopathy.
Our data highlight the role of RIPK1 kinase activity in promoting not
only both apoptosis and necroptosis but also transcriptional produc-
tion of pro-inflammatory cytokines, such as IL-6, which is a previously
underappreciated aspect of RIPK1 biology. These results suggest that
the periodic fevers of these patients may reflect the augmented produc-
tion of cytokines such as IL-6 in response to what may be benign stimuli
for normal individuals. Activated RIPK1 has been shown to mediate
transcription of pro-inflammatory cytokines in myeloid lineages, inde-
pendent of cell death, in neurodegenerative diseases^21 ,^22. In addition,
cytokines such as TNF in turn can further promote cell death, thus
establishing a vicious circle of inflammation that culminates in the
development of an autoinflammatory disease.
We show that patient fibroblasts may have developed several com-
pensatory mechanisms to protect against deleterious effects of acti-
vated RIPK1, including downregulating the expression of RIPK1 and
TNFR1, as well as promoting anti-ROS mechanisms. These findings
provide insights into the complex disease mechanisms behind non-
cleavable RIPK1 variants in humans compared to that of the mouse
models. Our study also linked an activating RIPK1 variant to ferroptosis,
which sheds light on the diverse roles of RIPK1 in regulating several
cell death pathways.
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availability are available at https://doi.org/10.1038/s41586-019-1830-y.
- Yuan, J., Amin, P. & Ofengeim, D. Necroptosis and RIPK1-mediated neuroinflammation in
CNS diseases. Nat. Rev. Neurosci. 20 , 19–33 (2019). - Zhang, X., Dowling, J. P. & Zhang, J. RIPK1 can mediate apoptosis in addition to
necroptosis during embryonic development. Cell Death Dis. 10 , 245 (2019). - Newton, K. et al. Cleavage of RIPK1 by caspase-8 is crucial for limiting apoptosis and
necroptosis. Nature 574 , 428–431 (2019). - Xu, D. et al. TBK1 suppresses RIPK1-driven apoptosis and inflammation during
development and in aging. Cell 1 74, 1477–1491 (2018). - Meng, H. et al. Death-domain dimerization-mediated activation of RIPK1 controls
necroptosis and RIPK1-dependent apoptosis. Proc. Natl Acad. Sci. USA 115 , E2001–E2009
(2018). - Lin, Y., Devin, A., Rodriguez, Y. & Liu, Z. G. Cleavage of the death domain kinase RIP by
caspase-8 prompts TNF-induced apoptosis. Genes Dev. 13 , 2514–2526 (1999). - Degterev, A. et al. Identification of RIP1 kinase as a specific cellular target of necrostatins.
Nat. Chem. Biol. 4 , 313–321 (2008). - Ofengeim, D. et al. Activation of necroptosis in multiple sclerosis. Cell Reports 10 ,
1836–1849 (2015). - Sun, L. et al. Mixed lineage kinase domain-like protein mediates necrosis signaling
downstream of RIP3 kinase. Cell 148 , 213–227 (2012). - Nigro, P., Pompilio, G. & Capogrossi, M. C. Cyclophilin A: a key player for human disease.
Cell Death Dis. 4 , e888 (2013). - Christofferson, D. E. & Yuan, J. Cyclophilin A release as a biomarker of necrotic cell death.
Cell Death Differ. 17 , 1942–1943 (2010). - Zhu, K. et al. Necroptosis promotes cell-autonomous activation of proinflammatory
cytokine gene expression. Cell Death Dis. 9 , 500 (2018). - Henry, C. M. & Martin, S. J. Caspase-8 acts in a non-enzymatic role as a SCAFFOLD for
assembly of a pro-inflammatory “FADDosome” complex upon TRAIL Stimulation. Mol.
Cell 65 , 715–729 (2017). - Ingold, I. et al. Selenium utilization by GPX4 Is required to prevent hydroperoxide-
induced ferroptosis. Cell 172 , 409–422 (2018). - Stockwell, B. R. et al. Ferroptosis: a regulated cell death nexus linking metabolism, redox
biology, and disease. Cell 171 , 273–285 (2017). - Dixon, S. J. & Stockwell, B. R. The role of iron and reactive oxygen species in cell death.
Nat. Chem. Biol. 10 , 9–17 (2014). - Zhang, D.-W. et al. RIP3, an energy metabolism regulator that switches TNF-induced cell
death from apoptosis to necrosis. Science 325 , 332–336 (2009). - Zhang, Y. et al. RIP1 autophosphorylation is promoted by mitochondrial ROS and is
essential for RIP3 recruitment into necrosome. Nat. Commun. 8 , 14329 (2017). - Cuchet-Lourenço, D. et al. Biallelic RIPK1 mutations in humans cause severe
immunodeficiency, arthritis, and intestinal inflammation. Science 361 , 810–813 (2018). - Li, Y. et al. Human RIPK1 deficiency causes combined immunodeficiency and
inflammatory bowel diseases. Proc. Natl Acad. Sci. USA 116 , 970–975 (2019). - Ito, Y. et al. RIPK1 mediates axonal degeneration by promoting inflammation and
necroptosis in ALS. Science 353 , 603–608 (2016). - Ofengeim, D. et al. RIPK1 mediates a disease-associated microglial response in
Alzheimer’s disease. Proc. Natl Acad. Sci. USA 114 , E8788–E8797 (2017).
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