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RNF31 promotes tumorigenesis via inhibiting RIPK1 kinase-dependent apoptosis

Oncogene volume 42, pages 1585–1596 (2023)Cite this article

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Abstract

It is well established that interferon (IFN) and tumor necrosis factor (TNF) could synergistically promote antitumor toxicity and avoid resistance of antigen-negative tumors during cancer immunotherapy. The linear ubiquitin chain assembly complex (LUBAC) has been widely known to regulate receptor-interacting protein kinase-1(RIPK1) kinase activity and TNF-mediated cell death during inflammation and embryogenesis. However, whether LUBAC and RIPK1 kinase activity in tumor microenvironment could regulate antitumor immunity are still not very clear. Here, we demonstrated a cancer cell-intrinsic role of LUBAC complex in tumor microenvironment to promote tumorigenesis. Lacking LUBAC component RNF31 in B16 melanoma cells but not immune cells including macrophages or dendritic cells greatly impaired tumor growth by increasing intratumoral CD8+ T cells infiltration. Mechanistically, we found that tumor cells without RNF31 shown severe apoptosis-mediated cell death caused by TNFα/IFNγ in the tumor microenvironment. Most importantly, we found that RNF31 could limit RIPK1 kinase activity and further prevent tumor cell death in a transcription-independent manner, suggesting a crucial role of RIPK1 kinase activity in tumorigenesis. Together, our results demonstrate an essential role of RNF31 and RIPK1 kinase activity in tumorigenesis and imply that RNF31 inhibition could be harnessed to enhance antitumor toxicity during tumor immunotherapy.

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Fig. 1: RNF31 in tumor cells is critical for tumorigenesis and antitumor immunity.
Fig. 2: RNF31 in macrophages or dendritic cells is dispensable for tumorigenesis and antitumor immunity.
Fig. 3: Loss of RNF31 promotes TNFα/IFNγ-induced RIPK1-kinase-dependent melanoma cell death.
Fig. 4: RNF31 regulates TNFα/IFNγ-induced tumor cell death in a transcription-independent manner.
Fig. 5: RNF31-mediated linear ubiquitination of RIPK1 limit RIPK1-kinase activity in tumor cell.

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The authors declare that the data supporting the findings of this study are available within the paper and its Supplementary Information Files.

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Acknowledgements

This work was partially supported by the grant from National Key Research and Development Program of China (2019YFA0508502 to Xin Lin), National Natural Science Foundation of China (31930039, 81630058, 91942303, 31821003 to XL, and 81971469, 31670904 to XZ), and annual funding from Tsinghua University-Peking University Jointed Center for Life Sciences.

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  1. These authors contributed equally: Jie Zhang, Hailin Tu.

Authors and Affiliations

  1. Institute for Immunology, School of Medicine, Tsinghua University, Beijing, China

    Jie Zhang, Hailin Tu, Zheyu Zheng, Xueqiang Zhao & Xin Lin

  2. Department of Basic Medical Sciences, Tsinghua University School of Medicine, Beijing, 100084, China

    Jie Zhang, Hailin Tu, Zheyu Zheng, Xueqiang Zhao & Xin Lin

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JZ, HT and XL conceived and designed the study. JZ performed most of experiments. HT and ZZ provided help for some experiments. JZ, HT and ZZ analyzed and interpreted data. JZ, HT and XL wrote the manuscript, with all authors contributing to writing and providing feedback.

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Correspondence to Xin Lin.

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Zhang, J., Tu, H., Zheng, Z. et al. RNF31 promotes tumorigenesis via inhibiting RIPK1 kinase-dependent apoptosis. Oncogene 42, 1585–1596 (2023). https://doi.org/10.1038/s41388-023-02669-8

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