Dr Qing Zhou’s team reveals that non-cleavable variants of RIPK1 cause a new dominant autoinflammatory disease
Source：Qing Zhou
2020-06-12
On January 2, 2020, the research team led by Dr. Qing Zhou at Life Sciences Institute, Zhejiang University, identified an early-onset autoinflammatory disorder caused by heterozygous mutations in the gene encoding RIPK1, an important regulator of apoptosis, necroptosis and innate immune signaling pathways, which was published in Nature (2020, 577: 109–114).
Activation of RIPK1 controls TNF-mediated apoptosis, necroptosis and inflammatory pathways. Cleavage of human and mouse RIPK1 after residues D324 and D325, respectively, by caspase-8 separates the RIPK1 kinase domain from the intermediate and death domains. The D325A mutation in mouse RIPK1 leads to embryonic lethality during mouse development. However, the functional importance of blocking caspase-8-mediated cleavage of RIPK1 on RIPK1 activation in humans is unknown.
Recently, Zhou’s group identified two families with variants in RIPK1 (D324V and D324H) that led to distinct symptoms of recurrent fevers and lymphadenopathy in an autosomal dominant manner. Impaired cleavage of RIPK1 D324 by caspase-8 sensitized patients’ peripheral blood mononuclear cells (PBMCs) to RIPK1 activation, apoptosis and necroptosis induced by TNF. The patients showed strong RIPK1-dependent activation of inflammatory signaling pathways and overproduction of inflammatory cytokines and chemokines compared with unaffected controls. Furthermore, they showed that expression of the RIPK1 mutants D325V or D325H in mouse embryonic fibroblasts conferred not only increased sensitivity to RIPK1 activation-mediated apoptosis and necroptosis, but also induction of pro-inflammatory cytokines such as IL-6 and TNF.
More excitingly, a patient experienced clinical improvement and the PBMCs displayed normalized expression of inflammatory mediators after treatment with tocilizumab (monoclonal antibody against IL-6R), supporting a pathogenic role of excessive IL-6 production in patient.
By contrast, they showed that patient fibroblasts may have developed several compensatory mechanisms to protect against deleterious effects of activated RIPK1, including downregulating the expression of RIPK1 and TNFR1, as well as promoting anti-ROS mechanisms. These findings provided insights into the complex disease mechanisms behind non-cleavable RIPK1 variants in humans compared to that of the mouse models. This study also linked an activating RIPK1 variant to ferroptosis, which sheds lights on the diverse roles of RIPK1 in regulating several cell death pathways.
Together, this research suggests that human non-cleavable RIPK1 variants promote activation of RIPK1, and lead to a new autoinflammatory disease characterized by hypersensitivity to apoptosis and necroptosis and increased inflammatory responses in peripheral blood mononuclear cells, as well as a compensatory mechanism to protect against several pro-death stimuli in fibroblasts.
This research was supported by National Key Research and Development Project, The National Natural Science Foundation of China, Zhejiang Provincial Natural Science Foundation of China and the Fundamental Research Funds for the Central Universities.
Links: https://www.nature.com/articles/s41586-019-1830-y
Activation of RIPK1 controls TNF-mediated apoptosis, necroptosis and inflammatory pathways. Cleavage of human and mouse RIPK1 after residues D324 and D325, respectively, by caspase-8 separates the RIPK1 kinase domain from the intermediate and death domains. The D325A mutation in mouse RIPK1 leads to embryonic lethality during mouse development. However, the functional importance of blocking caspase-8-mediated cleavage of RIPK1 on RIPK1 activation in humans is unknown.
Recently, Zhou’s group identified two families with variants in RIPK1 (D324V and D324H) that led to distinct symptoms of recurrent fevers and lymphadenopathy in an autosomal dominant manner. Impaired cleavage of RIPK1 D324 by caspase-8 sensitized patients’ peripheral blood mononuclear cells (PBMCs) to RIPK1 activation, apoptosis and necroptosis induced by TNF. The patients showed strong RIPK1-dependent activation of inflammatory signaling pathways and overproduction of inflammatory cytokines and chemokines compared with unaffected controls. Furthermore, they showed that expression of the RIPK1 mutants D325V or D325H in mouse embryonic fibroblasts conferred not only increased sensitivity to RIPK1 activation-mediated apoptosis and necroptosis, but also induction of pro-inflammatory cytokines such as IL-6 and TNF.
More excitingly, a patient experienced clinical improvement and the PBMCs displayed normalized expression of inflammatory mediators after treatment with tocilizumab (monoclonal antibody against IL-6R), supporting a pathogenic role of excessive IL-6 production in patient.
By contrast, they showed that patient fibroblasts may have developed several compensatory mechanisms to protect against deleterious effects of activated RIPK1, including downregulating the expression of RIPK1 and TNFR1, as well as promoting anti-ROS mechanisms. These findings provided insights into the complex disease mechanisms behind non-cleavable RIPK1 variants in humans compared to that of the mouse models. This study also linked an activating RIPK1 variant to ferroptosis, which sheds lights on the diverse roles of RIPK1 in regulating several cell death pathways.
Together, this research suggests that human non-cleavable RIPK1 variants promote activation of RIPK1, and lead to a new autoinflammatory disease characterized by hypersensitivity to apoptosis and necroptosis and increased inflammatory responses in peripheral blood mononuclear cells, as well as a compensatory mechanism to protect against several pro-death stimuli in fibroblasts.
This research was supported by National Key Research and Development Project, The National Natural Science Foundation of China, Zhejiang Provincial Natural Science Foundation of China and the Fundamental Research Funds for the Central Universities.
Links: https://www.nature.com/articles/s41586-019-1830-y
