{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRIPK1 serves as a pivotal adaptor and regulatory kinase in death receptor signaling, where its post‐translational modifications—especially ubiquitination by proteins such as cIAP1/2 and linkage‐specific ubiquitin chains—promote NF‑κB activation and cell survival. In this context, RIPK1’s ubiquitination (e.g. at Lys‑377) enables the recruitment of prosurvival complexes including TAK1 and the IKK complex, thereby orchestrating transcriptional programs that counterbalance death‐promoting signals. Thus, as a molecular “switch,” RIPK1 integrates extracellular cues into distinct cell fate decisions with its modifications providing a critical checkpoint between life and death."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nConversely, under conditions where ubiquitin‐modifying enzymes are inactivated or when caspase‑8 activity is compromised, RIPK1 shifts its role toward propagating cell death programs. In these settings, RIPK1 engages with RIPK3—via conserved RHIM domains—to nucleate the assembly of an amyloid‐like “necrosome” that drives necroptosis, a regulated form of inflammatory cell death. In addition, loss of RIPK1 ubiquitination or its caspase‑mediated cleavage can convert it into a proapoptotic adaptor that recruits caspase‑8, thereby triggering extrinsic apoptosis. Various stimuli such as tumor necrosis factor–related ligands, DNA damage and even viral infections (or viral evasion proteins) modulate these events, while small molecules (e.g. Necrostatin‑1) can inhibit RIPK1 kinase activity to block necroptosis. Collectively, these studies underscore how RIPK1 phosphorylation, cleavage and ubiquitination events finely tune the balance between prosurvival signaling and the activation of both apoptotic and necroptotic cell death pathways."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "38"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its direct regulation of cell death, RIPK1 exerts broader control over inflammatory and immune responses. By engaging in cytosolic sensor pathways (for example, linking with DAI in antiviral responses) and by modulating innate immune complexes, RIPK1 influences cytokine production in settings as diverse as neurodegeneration, cancer and atherosclerosis. Moreover, genetic deficiencies or non‐cleavable mutations of RIPK1 in mice and humans manifest as autoinflammatory disorders, immunodeficiency and aberrant cell death in multiple tissues, underscoring its central role as a checkpoint in immune homeostasis. These insights highlight RIPK1 as an attractive therapeutic target for conditions ranging from viral infections and cancer metastasis to chronic inflammatory diseases."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "39", "end_ref": "47"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Mathieu J M Bertrand, Snezana Milutinovic, Kathleen M Dickson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molcel.2008.05.014"}], "href": "https://doi.org/10.1016/j.molcel.2008.05.014"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18570872"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18570872"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Chee-Kwee Ea, Li Deng, Zong-Ping Xia, et al. 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