RIPK1 is a master regulator of multiple cell death pathways, including apoptosis and necroptosis, and inflammation. Importantly, activation of RIPK1 has also been shown to promote the transcriptional induction of proinflammatory cytokines in cells undergoing necroptosis, in animal models of amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease (AD), and in human ALS and AD. Rare human genetic carriers of non-cleavable RIPK1 variants (D324V and D324H) exhibit distinct symptoms of recurrent fevers and increased transcription of proinflammatory cytokines. Multiple RIPK1 inhibitors have been advanced into human clinical trials as new therapeutics for human inflammatory and neurodegenerative diseases, such as ALS and AD. However, it is unclear whether and how RIPK1 kinase activity directly mediates inflammation independent of cell death as the nuclear function of RIPK1 has not yet been explored. Here we show that nuclear RIPK1 is physically associated with the BAF complex. Upon RIPK1 activation, the RIPK1/BAF complex is recruited by specific transcription factors to active enhancers and promoters marked by H3K4me1 and H3K27ac. Activated nuclear RIPK1 mediates the phosphorylation of SMARCC2, a key component of the BAF complex, to promote chromatin remodeling and the transcription of specific proinflammatory genes. Increased nuclear RIPK1 activation and RIPK1/BAF-mediated chromatin-remodeling activity were found in cells expressing non-cleavable RIPK1, and increased enrichment of activated RIPK1 on active enhancers and promoters was found in an animal model and human pathological samples of ALS. Our results suggest that RIPK1 kinase serves as a transcriptional coregulator in nucleus that can transmit extracellular stimuli to the BAF complex to modulate chromatin accessibility and directly regulate the transcription of specific genes involved in mediating inflammatory responses.
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ATAC-seq, RNA-seq and CUT&Tag data have been deposited in the GEO database (http://www.ncbi.nlm.nih.gov/geo/) with an accession number GSE179018. All the codes used in the analysis are available upon request.
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We thank Dr. Kevin Struhl for critical reading of this manuscript. We thank Dr. Jianke Zhang of Thomas Jefferson University, for Ripk1D325A/D325A/Ripk3−/− MEFs, Dr. Matthew Frosch of Harvard Neuropathology Services for providing post-mortem human spinal cord pathological samples, Dr. Jennifer Walters at the Harvard Medical School Nikon microscope facility for assistance with fluorescence microscopy, Dr. Gary Kasof of Cell Signaling Technology for developing p-S306 SMARCC2 antibody and Prof. Jiahuai Han of Xiamen University for providing Ripk1D325A/D325A MEFs during revision. This work was supported in part by the National Natural Science Foundation of China (82188101, 21837004 and 91849204), and the National Natural Science Youth Foundation of China (31701210).
J.Y. is a consultant for Sanofi. The other authors declare that they have no competing financial interests.
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Li, W., Shan, B., Zou, C. et al. Nuclear RIPK1 promotes chromatin remodeling to mediate inflammatory response. Cell Res 32, 621–637 (2022). https://doi.org/10.1038/s41422-022-00673-3
Cell Research (2022)