2. Academic Validation
  3. PP6 negatively modulates LUBAC-mediated M1-ubiquitination of RIPK1 and c-FLIPL to promote TNFα-mediated cell death

PP6 negatively modulates LUBAC-mediated M1-ubiquitination of RIPK1 and c-FLIPL to promote TNFα-mediated cell death

  • Cell Death Dis. 2022 Sep 7;13(9):773. doi: 10.1038/s41419-022-05206-9.
Guowei Wu  # 1 2,  Dekang Li  # 1 2,  Wei Liang 1 2,  Weimin Sun 1 2,  Xingxing Xie 1 2,  Yilun Tong 1 2,  Bing Shan 1,  Mengmeng Zhang 1,  Xiaojuan Lu 1,  Junying Yuan 3,  Ying Li 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, 100049, 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. liying@sioc.ac.cn.
  • # Contributed equally.
PMID: 36071040 DOI: 10.1038/s41419-022-05206-9
Abstract

Activation of TNFR1 by TNFα induces the formation of a membrane-associated, intracellular complex termed complex I. Complex I orchestrates a complex pattern of modifications on key regulators of TNF signaling that collectively determines the cell fate by activating pro-survival or executing cell death programs. However, the regulatory mechanism of complex I in cell-fate decision is not fully understood. Here we identify protein phosphatase-6 (PP6) as a previously unidentified component of complex I. Loss of PP6 protects cells from TNFα-mediated cell death. The role of PP6 in regulating cell death requires its Phosphatase activity and regulatory subunits. Further mechanistic studies show that PP6 modulates LUBAC-mediated M1-ubiquitination of RIPK1 and c-FLIPL to promote RIPK1 activation and c-FLIPL degradation. We also show that melanoma-associated PP6 inactivating mutants offer resistance to cell death due to the loss of sensitivity to TNFα. Thus, our study provides a potential mechanism by which melanoma-related PP6 inactivating mutations promote Cancer progression.

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