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
  • 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. [email protected].
  • 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. [email protected].
  • # 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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