Glycosylation Network Research Center, Yonsei University, Seoul, Republic of Korea.
Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
Front Immunol. 2023 Jun 9;14:1160490. doi: 10.3389/fimmu.2023.1160490. eCollection 2023.
Necroptosis is a type of cell death with excessive inflammation and organ damage in various human diseases. Although abnormal necroptosis is common in patients with neurodegenerative, cardiovascular, and infectious diseases, the mechanisms by which -GlcNAcylation contributes to the regulation of necroptotic cell death are poorly understood. In this study, we reveal that -GlcNAcylation of RIPK1 (receptor-interacting protein kinase1) was decreased in erythrocytes of the mouse injected with lipopolysaccharide, resulting in the acceleration of erythrocyte necroptosis through increased formation of RIPK1-RIPK3 complex. Mechanistically, we discovered that -GlcNAcylation of RIPK1 at serine 331 in human (corresponding to serine 332 in mouse) inhibits phosphorylation of RIPK1 at serine 166, which is necessary for the necroptotic activity of RIPK1 and suppresses the formation of the RIPK1-RIPK3 complex in MEFs. Thus, our study demonstrates that RIPK1 -GlcNAcylation serves as a checkpoint to suppress necroptotic signaling in erythrocytes.
细胞坏死是一种伴有过度炎症和各种人类疾病中器官损伤的细胞死亡形式。虽然异常细胞坏死在神经退行性、心血管和传染病患者中很常见，但 -GlcNAc 化如何有助于调节细胞坏死的机制还知之甚少。在这项研究中，我们揭示了脂多糖注射小鼠的红细胞中 RIPK1（受体相互作用蛋白激酶 1）的 -GlcNAc 化减少，导致通过增加 RIPK1-RIPK3 复合物的形成加速红细胞坏死。从机制上讲，我们发现在人类 RIPK1 的丝氨酸 331（对应于小鼠的丝氨酸 332）上的 -GlcNAc 化抑制了 RIPK1 丝氨酸 166 的磷酸化，这对于 RIPK1 的坏死活性是必需的，并抑制了 MEFs 中 RIPK1-RIPK3 复合物的形成。因此，我们的研究表明，RIPK1 的 -GlcNAc 化作为抑制红细胞坏死信号的检查点。
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