Receptor interacting protein kinase 1 (RIPK1) has emerged as a key regulatory molecule that influences the balance between cell death and cell survival. Under external stress, RIPK1 determines whether a cell undergoes RIPK-dependent apoptosis (RDA) or survives by activating NF-κB signaling. However, the role and mechanisms of RIPK1 on sunitinib sensitivity in renal cell carcinoma (RCC) remain elusive. In this study, we demonstrated that the O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) of RIPK1 induces sunitinib resistance in RCC by inhibiting RDA. O-GlcNAc transferase (OGT) specifically interacts with RIPK1 through its tetratricopeptide repeats (TPR) domain and facilitates RIPK1 O-GlcNAcylation. The O-GlcNAcylation of RIPK1 at Ser331, Ser440 and Ser669 regulates RIPK1 ubiquitination and the formation of the RIPK1/FADD/Caspase-8 complex, thereby inhibiting sunitinib-induced RDA in RCC. Site-specific depletion of O-GlcNAcylation on RIPK1 affects the formation of the RIPK1/FADD/Caspase 8 complex, leading to increased sunitinib sensitivity in RCC.

中文翻译：

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RIPK1 依赖性细胞凋亡的 O-GlcNAcylation 调节决定了肾细胞癌对舒尼替尼的敏感性


受体相互作用蛋白激酶 1 （RIPK1） 已成为影响细胞死亡和细胞存活之间平衡的关键调节分子。在外部应激下，RIPK1 通过激活 NF-κB 信号转导来确定细胞是经历 RIPK 依赖性细胞凋亡 （RDA） 还是存活。然而，RIPK1 对肾细胞癌 （RCC） 舒尼替尼敏感性的作用和机制仍然难以捉摸。在这项研究中，我们证明了 RIPK1 的 O 连接 β-N-乙酰葡糖胺修饰 （O-GlcNAcylation） 通过抑制 RDA 诱导 RCC 中的舒尼替尼耐药。O-GlcNAc 转移酶 （OGT） 通过其四肽重复序列 （TPR） 结构域与 RIPK1 特异性相互作用，并促进 RIPK1 O-GlcNAcylation。RIPK1 在 Ser331、Ser440 和 Ser669 位点的 O-GlcNAcylation 调节 RIPK1 泛素化和 RIPK1/FADD/Caspase-8 复合物的形成，从而抑制舒尼替尼诱导的 RCC RDA。RIPK1 上 O-GlcNAcylation 的位点特异性耗竭会影响 RIPK1/FADD/Caspase 8 复合物的形成，导致 RCC 中舒尼替尼的敏感性增加。