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.

RIPK1 是多种细胞死亡途径的主要调节因子，包括细胞凋亡、坏死性凋亡以及炎症。重要的是，RIPK1 的激活也被证明可以促进坏死性凋亡细胞、肌萎缩侧索硬化症 (ALS) 和阿尔茨海默病 (AD) 动物模型以及人类 ALS 和 AD 中促炎细胞因子的转录诱导。不可裂解的 RIPK1 变体（D324V 和 D324H）的罕见人类遗传携带者表现出反复发烧和促炎细胞因子转录增加的明显症状。多种 RIPK1 抑制剂已进入人体临床试验，作为人类炎症和神经退行性疾病（如 ALS 和 AD）的新疗法。然而，由于 RIPK1 的核功能尚未被探索，因此尚不清楚 RIPK1 激酶活性是否以及如何直接介导独立于细胞死亡的炎症。在这里，我们证明核 RIPK1 与 BAF 复合体物理相关。RIPK1 激活后，特定转录因子将 RIPK1/BAF 复合物募集至由 H3K4me1 和 H3K27ac 标记的活性增强子和启动子。激活的核 RIPK1 介导 SMARCC2（BAF 复合物的关键成分）的磷酸化，以促进染色质重塑和特定促炎基因的转录。在表达不可裂解 RIPK1 的细胞中发现核 RIPK1 激活和 RIPK1/BAF 介导的染色质重塑活性增加，在 ALS 动物模型和人类病理样本中发现激活的 RIPK1 在活性增强子和启动子上的富集增加。我们的结果表明，RIPK1 激酶作为细胞核中的转录共调节因子，可以将细胞外刺激传递到 BAF 复合体，以调节染色质可及性并直接调节参与介导炎症反应的特定基因的转录。