2. Academic Validation
  3. Quantitative analysis of phosphoproteome in necroptosis reveals a role of TRIM28 phosphorylation in promoting necroptosis-induced cytokine production

Quantitative analysis of phosphoproteome in necroptosis reveals a role of TRIM28 phosphorylation in promoting necroptosis-induced cytokine production

  • Cell Death Dis. 2021 Oct 23;12(11):994. doi: 10.1038/s41419-021-04290-7.
Rui Zu  # 1 2,  Zhen Yu  # 1 2,  Jing Zhao 1 2,  Xiaojuan Lu 1,  Wei Liang 1 2,  Le Sun 1 2,  Chenfang Si 1 2,  Kezhou Zhu 1 2,  Tian Zhang 1 2,  Ganquan Li 1 2,  Mengmeng Zhang 1,  Yaoyang Zhang 1,  Nan Liu 1,  Junying Yuan 3,  Bing Shan 4
Affiliations

Affiliations

  • 1 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 100 Haike Road, PuDong District, 201210, Shanghai, China.
  • 2 University of Chinese Academy of Sciences, Beijing, China.
  • 3 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 100 Haike Road, PuDong District, 201210, Shanghai, China. junying_yuan@sioc.ac.cn.
  • 4 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 100 Haike Road, PuDong District, 201210, Shanghai, China. shanbing@sioc.ac.cn.
  • # Contributed equally.
PMID: 34689152 DOI: 10.1038/s41419-021-04290-7
Abstract

Necroptosis is a form of regulated necrotic cell death that promotes inflammation. In cells undergoing Necroptosis, activated RIPK1 kinase mediates the formation of RIPK1/RIPK3/MLKL complex to promote MLKL oligomerization and execution of Necroptosis. RIPK1 kinase activity also promotes cell-autonomous activation of proinflammatory cytokine production in Necroptosis. However, the signaling pathways downstream of RIPK1 kinase in Necroptosis and how RIPK1 kinase activation controls inflammatory response induced by Necroptosis are still largely unknown. Here, we quantitatively measured the temporal dynamics of over 7000 confident phosphorylation-sites during Necroptosis using mass spectrometry. Our study defined a RIPK1-dependent phosphorylation pattern in late Necroptosis that is associated with a proinflammatory component marked by p-S473 TRIM28. We show that the activation of p38 MAPK mediated by oligomerized MLKL promotes the phosphorylation of S473 TRIM28, which in turn mediates inflammation during late Necroptosis. Taken together, our study illustrates a mechanism by which p38 MAPK may be activated by oligomerized MLKL to promote inflammation in Necroptosis.

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