TBK1 Suppresses RIPK1-Driven Apoptosis and Inflammation during Development and in Aging.

Aging is a major risk factor for both genetic and sporadic neurodegenerative disorders. However, it is unclear how aging interacts with genetic predispositions to promote neurodegeneration. Here, we investigate how partial loss of function of TBK1, a major genetic cause for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) comorbidity, leads to age-dependent neurodegeneration. We show that TBK1 is an endogenous inhibitor of RIPK1 and the embryonic lethality of Tbk1-/- mice is dependent on RIPK1 kinase activity. In aging human brains, another endogenous RIPK1 inhibitor, TAK1, exhibits a marked decrease in expression. We show that in Tbk1+/- mice, the reduced myeloid TAK1 expression promotes all the key hallmarks of ALS/FTD, including neuroinflammation, TDP-43 aggregation, axonal degeneration, neuronal loss, and behavior deficits, which are blocked upon inhibition of RIPK1. Thus, aging facilitates RIPK1 activation by reducing TAK1 expression, which cooperates with genetic risk factors to promote the onset of ALS/FTD.

G3BP1 promotes DNA binding and activation of cGAS.

Cyclic GMP-AMP synthase (cGAS) is a key sensor responsible for cytosolic DNA detection. Here we report that GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) is critical for DNA sensing and efficient activation of cGAS. G3BP1 enhanced DNA binding of cGAS by promoting the formation of large cGAS complexes. G3BP1 deficiency led to inefficient DNA binding by cGAS and inhibited cGAS-dependent interferon (IFN) production. The G3BP1 inhibitor epigallocatechin gallate (EGCG) disrupted existing G3BP1-cGAS complexes and inhibited DNA-triggered cGAS activation, thereby blocking DNA-induced IFN production both in vivo and in vitro. EGCG administration blunted self DNA-induced autoinflammatory responses in an Aicardi-Goutières syndrome (AGS) mouse model and reduced IFN-stimulated gene expression in cells from a patient with AGS. Thus, our study reveals that G3BP1 physically interacts with and primes cGAS for efficient activation. Furthermore, EGCG-mediated inhibition of G3BP1 provides a potential treatment for cGAS-related autoimmune diseases.

A dominant autoinflammatory disease caused by non-cleavable variants of RIPK1.

Activation of RIPK1 controls TNF-mediated apoptosis, necroptosis and inflammatory pathways1. 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 development2,3. However, the functional importance of blocking caspase-8-mediated cleavage of RIPK1 on RIPK1 activation in humans is unknown. Here we identify two families with variants in RIPK1 (D324V and D324H) that lead to distinct symptoms of recurrent fevers and lymphadenopathy in an autosomal-dominant manner. Impaired cleavage of RIPK1 D324 variants by caspase-8 sensitized patients' peripheral blood mononuclear cells to RIPK1 activation, apoptosis and necroptosis induced by TNF. The patients showed strong RIPK1-dependent activation of inflammatory signalling pathways and overproduction of inflammatory cytokines and chemokines compared with unaffected controls. Furthermore, we show that expression of the RIPK1 mutants D325V or D325H in mouse embryonic fibroblasts confers not only increased sensitivity to RIPK1 activation-mediated apoptosis and necroptosis, but also induction of pro-inflammatory cytokines such as IL-6 and TNF. By contrast, patient-derived fibroblasts showed reduced expression of RIPK1 and downregulated production of reactive oxygen species, resulting in resistance to necroptosis and ferroptosis. Together, these data suggest that human non-cleavable RIPK1 variants promote activation of RIPK1, and lead to an autoinflammatory disease characterized by hypersensitivity to apoptosis and necroptosis and increased inflammatory response in peripheral blood mononuclear cells, as well as a compensatory mechanism to protect against several pro-death stimuli in fibroblasts.

Chromodomain Protein CDYL Acts as a Crotonyl-CoA Hydratase to Regulate Histone Crotonylation and Spermatogenesis.

Lysine crotonylation (Kcr) is a newly identified histone modification that is associated with active transcription in mammalian cells. Here we report that the chromodomain Y-like transcription corepressor CDYL negatively regulates histone Kcr by acting as a crotonyl-CoA hydratase to convert crotonyl-CoA to ß-hydroxybutyryl-CoA. We showed that the negative regulation of histone Kcr by CDYL is intrinsically linked to its transcription repression activity and functionally implemented in the reactivation of sex chromosome-linked genes in round spermatids and genome-wide histone replacement in elongating spermatids. Significantly, Cdyl transgenic mice manifest dysregulation of histone Kcr and reduction of male fertility with a decreased epididymal sperm count and sperm cell motility. Our study uncovers a biochemical pathway in the regulation of histone Kcr and implicates CDYL-regulated histone Kcr in spermatogenesis, adding to the understanding of the physiology of male reproduction and the mechanism of the spermatogenic failure in AZFc (Azoospermia Factor c)-deleted infertile men.

Sequential activation of necroptosis and apoptosis cooperates to mediate vascular and neural pathology in stroke.

Apoptosis and necroptosis are two regulated cell death mechanisms; however, the interaction between these cell death pathways in vivo is unclear. Here we used cerebral ischemia/reperfusion as a model to investigate the interaction between apoptosis and necroptosis. We show that the activation of RIPK1 sequentially promotes necroptosis followed by apoptosis in a temporally specific manner. Cerebral ischemia/reperfusion insult rapidly activates necroptosis to promote cerebral hemorrhage and neuroinflammation. Ripk3 deficiency reduces cerebral hemorrhage and delays the onset of neural damage mediated by inflammation. Reduced cerebral perfusion resulting from arterial occlusion promotes the degradation of TAK1, a suppressor of RIPK1, and the transition from necroptosis to apoptosis. Conditional knockout of TAK1 in microglial/infiltrated macrophages and neuronal lineages sensitizes to ischemic infarction by promoting apoptosis. Taken together, our results demonstrate the critical role of necroptosis in mediating neurovascular damage and hypoperfusion-induced TAK1 loss, which subsequently promotes apoptosis and cerebral pathology in stroke and neurodegeneration.

SCF(JFK) is a bona fide E3 ligase for ING4 and a potent promoter of the angiogenesis and metastasis of breast cancer.

Loss of function/dysregulation of inhibitor of growth 4 (ING4) and hyperactivation of NF-κB are frequent events in many types of human malignancies. However, the molecular mechanisms underlying these remarkable aberrations are not understood. Here, we report that ING4 is physically associated with JFK. We demonstrated that JFK targets ING4 for ubiquitination and degradation through assembly of an Skp1-Cul1-F-box (SCF) complex. We showed that JFK-mediated ING4 destabilization leads to the hyperactivation of the canonical NF-κB pathway and promotes angiogenesis and metastasis of breast cancer. Significantly, the expression of JFK is markedly up-regulated in breast cancer, and the level of JFK is negatively correlated with that of ING4 and positively correlated with an aggressive clinical behavior of breast carcinomas. Our study identified SCF(JFK) as a bona fide E3 ligase for ING4 and unraveled the JFK-ING4-NF-κB axis as an important player in the development and progression of breast cancer, supporting the pursuit of JFK as a potential target for breast cancer intervention.

Facile Synthesis of Sugar Nucleotides from Common Sugars by the Cascade Conversion Strategy.

Sugar nucleotides are essential glycosylation donors in the carbohydrate metabolism. Naturally, most sugar nucleotides are derived from a limited number of common sugar nucleotides by de novo biosynthetic pathways, undergoing single or multiple reactions such as dehydration, epimerization, isomerization, oxidation, reduction, amination, and acetylation reactions. However, it is widely believed that such complex bioconversions are not practical for synthetic use due to the high preparation cost and great difficulties in product isolation. Therefore, most of the discovered sugar nucleotides are not readily available. Here, based on de novo biosynthesis mainly, 13 difficult-to-access sugar nucleotides were successfully prepared from two common sugars D-Man and sucrose in high yields, at a multigram scale, and without the need for tedious purification manipulations. This work demonstrated that de novo biosynthesis, although undergoing complex reactions, is also practical and cost-effective for synthetic use by employing a cascade conversion strategy.

MBD3 promotes hepatocellular carcinoma progression and metastasis through negative regulation of tumour suppressor TFPI2.

BACKGROUND: The mechanism of recurrence and metastasis of hepatocellular carcinoma (HCC) is complex and challenging. Methyl-CpG binding domain protein 3 (MBD3) is a key epigenetic regulator involved in the progression and metastasis of several cancers, but its role in HCC remains unknown. METHODS: MBD3 expression in HCC was detected by immunohistochemistry and its association with clinicopathological features and patient's survival was analysed. The effects of MBD3 on hepatoma cells growth and metastasis were investigated, and the mechanism was explored. RESULTS: MBD3 is significantly highly expressed in HCC, associated with the advanced tumour stage and poor prognosis in HCC patients. MBD3 promotes the growth, angiogenesis and metastasis of HCC cells by inhibiting the tumour suppressor tissue factor pathway inhibitor 2 (TFPI2). Mechanistically, MBD3 can inhibit the TFPI2 transcription via the Nucleosome Remodeling and Deacetylase (NuRD) complex-mediated deacetylation, thus reactivating the activity of matrix metalloproteinases (MMPs) and PI3K/AKT signaling pathway, leading to the progression and metastasis of HCC CONCLUSIONS: Our results unravel the novel regulatory function of MBD3 in the progression and metastasis of HCC and identify MBD3 as an independent unfavourable prognostic factor for HCC patients, suggesting its potential as a promising therapeutic target as well.

Destabilizing LSD1 by Jade-2 promotes neurogenesis: an antibraking system in neural development.

Histone H3K4 demethylase LSD1 plays an important role in stem cell biology, especially in the maintenance of the silencing of differentiation genes. However, how the function of LSD1 is regulated and the differentiation genes are derepressed are not understood. Here, we report that elimination of LSD1 promotes embryonic stem cell (ESC) differentiation toward neural lineage. We showed that the destabilization of LSD1 occurs posttranscriptionally via the ubiquitin-proteasome pathway by an E3 ubiquitin ligase, Jade-2. We demonstrated that Jade-2 is a major LSD1 negative regulator during neurogenesis in vitro and in vivo in both mouse developing cerebral cortices and zebra fish embryos. Apparently, Jade-2-mediated degradation of LSD1 acts as an antibraking system and serves as a quick adaptive mechanism for re-establishing epigenetic landscape without more laborious transcriptional regulations. As a potential anticancer strategy, Jade-2-mediated LSD1 degradation could potentially be used in neuroblastoma cells to induce differentiation toward postmitotic neurons.

Cofactor-Driven Cascade Reactions Enable the Efficient Preparation of Sugar Nucleotides.

Glycosylation is catalyzed by glycosyltransferases using sugar nucleotides or occasionally lipid-linked phosphosugars as donors. However, only very few common sugar nucleotides that occur in humans can be obtained readily, while the majority of sugar nucleotides that exist in bacteria, plants, archaea, or viruses cannot be synthesized in sufficient quantities by either enzymatic or chemical synthesis. The limited availability of such rare sugar nucleotides is one of the major obstacles that has greatly hampered progress in glycoscience. Herein we describe a general cofactor-driven cascade conversion strategy for the efficient synthesis of sugar nucleotides. The described strategy allows the large-scale preparation of rare sugar nucleotides from common sugars in high yields and without the need for tedious purification processes.

Diversity-Oriented Chemoenzymatic Synthesis of Sulfated and Nonsulfated Core 2 O-GalNAc Glycans.

A diversity-oriented chemoenzymatic approach for the collective preparation of sulfated core 2 O-GalNAc glycans and their nonsulfated counterparts was described. A sulfated trisaccharide and a nonsulfated trisaccharide were chemically synthesized by combining flexible protected group manipulations and sequential one-pot glycosylations. The divergent enzymatic extension of these two trisaccharides, using a panel of robust glycosyltransferases that can recognize sulfated substrates and differentiating the branches with specifically designed glycosylation sequences to achieve regioselective sialylation, provided 36 structurally well-defined O-GalNAc glycans.

Identification of a 35S U4/U6.U5 tri-small nuclear ribonucleoprotein (tri-snRNP) complex intermediate in spliceosome assembly.

The de novo assembly and post-splicing reassembly of the U4/U6.U5 tri-snRNP remain to be investigated. We report here that ZIP, a protein containing a CCCH-type zinc finger and a G-patch domain, as characterized by us previously, regulates pre-mRNA splicing independent of RNA binding. We found that ZIP physically associates with the U4/U6.U5 tri-small nuclear ribonucleoprotein (tri-snRNP). Remarkably, the ZIP-containing tri-snRNP, which has a sedimentation coefficient of ∼35S, is a tri-snRNP that has not been described previously. We also found that the 35S tri-snRNP contains hPrp24, indicative of a state in which the U4/U6 di-snRNP is integrating with the U5 snRNP. We found that the 35S tri-snRNP is enriched in the Cajal body, indicating that it is an assembly intermediate during 25S tri-snRNP maturation. We showed that the 35S tri-snRNP also contains hPrp43, in which ATPase/RNA helicase activities are stimulated by ZIP. Our study identified, for the first time, a tri-snRNP intermediate, shedding new light on the de novo assembly and recycling of the U4/U6.U5 tri-snRNP.

JMJD6 promotes melanoma carcinogenesis through regulation of the alternative splicing of PAK1, a key MAPK signaling component.

BACKGROUND: Melanoma, originated from melanocytes located on the basal membrane of the epithelial tissue, is the most aggressive form of skin cancer that accounts for 75% of skin cancer-related death. Although it is believed that BRAF mutation and the mitogen-activated protein kinase (MAPK) pathway play critical roles in the pathogenesis of melanoma, how the MAPK signaling is regulated in melanoma carcinogenesis is still not fully understood. METHODS: We characterized JMJD6 expression in melanoma tissue array by immunohistochemistry analysis. We used human melanoma A375, 451Lu and SK-MEL-1 cell lines for in vitro proliferation and invasion experiments, and xenograft transplanted mice using murine melanoma B16F10 cells by bioluminescence imaging for in vivo tumor growth and pulmonary metastasis assessments. Endothelial tube formation assay, chicken yolk sac membrane assay and matrigel plug assay were performed to test the effect of JMJD6 on the angiogenic potential in vitro and in vivo. RESULTS: Here we report that the jumonji C domain-containing demethylase/hydroxylase JMJD6 is markedly up-regulated in melanoma. We found that high expression of JMJD6 is closely correlated with advanced clinicopathologic stage, aggressiveness, and poor prognosis of melanoma. RNA-seq showed that knockdown of JMJD6 affects the alternative splicing of a panel of transcripts including that encoding for PAK1, a key component in MAPK signaling pathway. We demonstrated that JMJD6 enhances the MAPK signaling and promotes multiple cellular processes including melanogenesis, proliferation, invasion, and angiogenesis in melanoma cells. Interestingly, JMJD6 is transcriptionally activated by c-Jun, generating a feedforward loop to drive the development and progression of melanoma. CONCLUSIONS: Our results indicate that JMJD6 is critically involved in melanoma carcinogenesis, supporting the pursuit of JMJD6 as a potential biomarker for melanoma aggressiveness and a target for melanoma intervention.

JMJD6 promotes colon carcinogenesis through negative regulation of p53 by hydroxylation.

Jumonji domain-containing 6 (JMJD6) is a member of the Jumonji C domain-containing family of proteins. Compared to other members of the family, the cellular activity of JMJD6 is still not clearly defined and its biological function is still largely unexplored. Here we report that JMJD6 is physically associated with the tumor suppressor p53. We demonstrated that JMJD6 acts as an α-ketoglutarate- and Fe(II)-dependent lysyl hydroxylase to catalyze p53 hydroxylation. We found that p53 indeed exists as a hydroxylated protein in vivo and that the hydroxylation occurs mainly on lysine 382 of p53. We showed that JMJD6 antagonizes p53 acetylation, promotes the association of p53 with its negative regulator MDMX, and represses transcriptional activity of p53. Depletion of JMJD6 enhances p53 transcriptional activity, arrests cells in the G1 phase, promotes cell apoptosis, and sensitizes cells to DNA damaging agent-induced cell death. Importantly, knockdown of JMJD6 represses p53-dependent colon cell proliferation and tumorigenesis in vivo, and significantly, the expression of JMJD6 is markedly up-regulated in various types of human cancer especially in colon cancer, and high nuclear JMJD6 protein is strongly correlated with aggressive clinical behaviors of colon adenocarcinomas. Our results reveal a novel posttranslational modification for p53 and support the pursuit of JMJD6 as a potential biomarker for colon cancer aggressiveness and a potential target for colon cancer intervention.

PAAT, a novel ATPase and trans-regulator of mitochondrial ABC transporters, is critically involved in the maintenance of mitochondrial homeostasis.

ATP-binding cassette (ABC) transporters are implicated in a diverse range of physiological and pathophysiological processes, such as cholesterol and lipid transportation and multidrug resistance. Despite the considerable efforts made in understanding of the cellular function of ABC proteins, the regulation mechanism of this type of protein is still poorly defined. Here we report the identification and functional characterization of a novel ATPase protein, protein associated with ABC transporters (PAAT), in humans. PAAT contains a nucleotide-binding domain (NBD)-like domain and a signal for intramitochondrial sorting. We showed that PAAT is localized in both the cytoplasm and the mitochondria and has an intrinsic ATPase activity. PAAT physically interacts with the 3 known mitochondrial inner membrane ABC proteins, ABCB7, ABCB8, and ABCB10, but not ABCB1, ABCB6, or ABCG2, and functionally regulates the transport of ferric nutrients and heme biosynthesis. Significantly, PAAT deficiency promotes cell death, reduces mitochondrial potential, and sensitizes mitochondria to oxidative stress-induced DNA damages. Our experiments revealed that PAAT is a novel ATPase and a trans-regulator of mitochondrial ABC transporters that plays an important role in the maintenance of mitochondrial homeostasis and cell survival.

Exosomal lncRNA ROR1-AS1 from cancer-associated fibroblasts inhibits ferroptosis of lung cancer cells through the IGF2BP1/SLC7A11 signal axis.

BACKGROUND: Targeting ferroptosis is a potential strategy for cancer treatment. Activated cancer-associated fibroblasts (CAFs) can affect the progression of lung cancer through exosomes. This study investigated the mechanism by which exosomal lncRNA ROR1-AS1 derived from CAFs affects ferroptosis of lung cancer cells. METHODS: CAFs were identified by western blot and immunofluorescence. Exosomes derived from CAFs (CAF-exo) were analyzed by transmission electron microscope, nanoparticle tracking analysis and western blot. The expression levels of ROR1-AS1, IGF2BP1 and SLC7A11 in lung cancer were analyzed by bioinformatics analysis and detected by qPCR and western blot. The lung cancer cells were treated with Erastin and/or CAF-exo, then cell viability was detected by cell counting kit-8, and the ferroptosis-related indicators were detected by corresponding kits. The relationship between IGF2BP1 and ROR1-AS1 or SLC7A11 was determined by RNA pull down and RNA immunoprecipitation, and their effects on cell ferroptosis were confirmed by rescue experiments. Xenotransplantation experiment was used to determine the effect of CAF-exo on tumor growth and ferroptosis in vivo. Immunohistochemistry was used to identify the Ki-67 and 4-HNE expression. RESULTS: ROR1-AS1, IGF2BP1 and SLC7A11 were upregulated in lung cancer and indicated poor prognosis. LncRNA ROR1-AS1 increased the stability of SLC7A11 mRNA by interacting with IGF2BP1. Exosomal ROR1-AS1 from CAFs inhibited ferroptosis of lung cancer cells in vitro and in vivo. The effect of ROR1-AS1 overexpression or IGF2BP1 overexpression on ferroptosis of lung cancer cells was partially reversed by IGF2BP1 silencing or SLC7A11 inhibition. CONCLUSIONS: CAFs secrete exosomal ROR1-AS1 to promote the expression of SLC7A11 by interacting with IGF2BP1, thereby inhibiting ferroptosis of lung cancer cells.

Targeting RIPK1 kinase for modulating inflammation in human diseases.

Receptor-Interacting Serine/Threonine-Protein Kinase 1 (RIPK1) is a master regulator of TNFR1 signaling in controlling cell death and survival. While the scaffold of RIPK1 participates in the canonical NF-κB pathway, the activation of RIPK1 kinase promotes not only necroptosis and apoptosis, but also inflammation by mediating the transcriptional induction of inflammatory cytokines. The nuclear translocation of activated RIPK1 has been shown to interact BAF-complex to promote chromatin remodeling and transcription. This review will highlight the proinflammatory role of RIPK1 kinase with focus on human neurodegenerative diseases. We will discuss the possibility of targeting RIPK1 kinase for the treatment of inflammatory pathology in human diseases.

Insights into the Mechanism of Graphene Acting on Water and Chloride Ion Permeability of Cement-Based Materials.

Due to its excellent mechanical properties and high aspect ratio, graphene can significantly improve the water and chloride ion permeability resistance of cementitious materials. However, few studies have investigated the effect of graphene size on the water and chloride ion permeability resistance of cementitious materials. The main issues are as follows: How do different sizes of graphene affect the water and chloride ion permeability resistance of cement-based materials, and by what means do they affect these properties? To address these issues, in this paper, two different sizes of graphene were used to prepare graphene dispersion, which was then mixed with cement to make graphene-reinforced cement-based materials. The permeability and microstructure of samples were investigated. Results show that the addition of graphene effectively improved both the water and chloride ion permeability resistance of cement-based materials significantly. The SEM (scanning electron microscope) images and XRD (X-ray diffraction) analysis show that the introduction of either type of graphene could effectively regulate the crystal size and morphology of hydration products and reduce the crystal size and the number of needle-like and rod-like hydration products. The main types of hydrated products are calcium hydroxide, ettringite, etc. The template effect of large-size graphene was more obvious, and a large number of regular flower-like cluster hydration products were formed, which made the structure of cement paste more compact and thus significantly improved the resistance to the penetration of water and chloride ions into the matrix of the concrete.

Comparing the diagnostic accuracy of telemedicine utilization versus in-person clinical examination for retinopathy of prematurity in premature infants: a systematic review.

PURPOSE: To synthesize the literature assessing the diagnostic accuracy of telemedicine evaluation compared with clinical examination for retinopathy of prematurity (ROP) in premature infants. METHODS: Covidence software was used to conduct a systematic literature search from September 14, 2020, through September 27, 2020, on MEDLINE (Ovid), EMBASE (Ovid), CINAHL, and the gray literature to identify studies relevant to telemedicine utilization for ROP detection. After duplicate removal and two-levels of screening, studies comparing telemedicine evaluation with binocular indirect ophthalmoscopic examination were included. Risk of bias assessment was conducted for the included studies following data extraction. A qualitative review was performed to summarize estimates of accuracy of ROP evaluation by telemedicine. RESULTS: A total of 507 studies were reviewed, of which 323 were found in EMBASE, 115 in MEDLINE, and 79 in CINAHL. Three possibly relevant conference abstracts were found. Following duplicate removal, 410 studies were reviewed based on titles and abstracts. Subsequently, 19 articles were thoroughly examined, and 14 studies (2,655 participants) were included. Most studies found that telemedicine performance for detecting ROP was comparable to ophthalmic examination, especially with regard to identifying treatment-requiring ROP. CONCLUSIONS: Telemedicine evaluation can reliably detect ROP. Incorporation of telemedicine into conventional neonatal care has the potential to improve access to ROP care.

Nuclear RIPK1 promotes chromatin remodeling to mediate inflammatory response.

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.