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DCAF12 promotes apoptosis and inhibits NF-κB activation by acting as an endogenous antagonist of IAPs

Oncogene volume 41, pages 3000–3010 (2022)Cite this article

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Abstract

Members of the Inhibitor of Apoptosis Protein (IAP) family are essential for cell survival and appear to neutralize the cell death machinery by binding pro-apoptotic caspases. dcaf12 was recently identified as an apoptosis regulator in Drosophila. However, the underlying molecular mechanisms are unknown. Here we revealed that human DCAF12 homolog binds multiple IAPs, including XIAP, cIAP1, cIAP2, and BRUCE, through recognition of BIR domains in IAPs. The pro-apoptotic function of DCAF12 is dependent on its capacity to bind IAPs. In response to apoptotic stimuli, DCAF12 translocates from the nucleus to the cytoplasm, where it blocks the interaction between XIAP and pro-apoptotic caspases to facilitate caspase activation and apoptosis execution. Similarly, DCAF12 suppresses NF-κB activation in an IAP binding-dependent manner. Moreover, DCAF12 acts as a tumor suppressor to restrict the malignant phenotypes of cancer cells. Together, our results suggest that DCAF12 is an evolutionarily conserved IAP antagonist.

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Fig. 1: DCAF12 interacts with multiple IAPs.
Fig. 2: DCAF12 has no impact on IAP proteins stability.
Fig. 3: Identification of the mutual-binding regions of DCAF12 and IAPs.
Fig. 4: DCAF12 promotes apoptosis by blocking the interactions between IAPs and caspases.
Fig. 5: DCAF12 negatively regulates TNFα-induced NF-κB pathway activation.
Fig. 6: DCAF12 translocates from the nucleus to the cytoplasm in response to apoptotic signal.
Fig. 7: DCAF12 suppresses the malignant phenotypes of cancer cells.

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Acknowledgements

We thank Dr. Mikihiko Naito for providing BRUCE cDNAs. This work was in part supported by the National Natural Science Foundation of China (No. 91957125, 81972396, 81672558 to CW; No. 91954106, 81872109 to KG.; No. 81872260, 81572768 to PZ) the Natural Science Foundation of Shanghai (No. 22ZR1449200 to KG; 22ZR1406600 to CW), the Natural Science Foundation of Shandong Province (No. ZR2021MH212 to LL), the Open Research Fund of State Key Laboratory of Genetic Engineering, Fudan University (No. SKLGE-2111 to KG), the Science and Technology Research Program of Shanghai (No. 9DZ2282100).

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  1. These authors contributed equally: Dongyue Jiao, Yingji Chen.

Authors and Affiliations

  1. Shanghai Stomatological Hospital & School of Stomatology, State Key Laboratory of Genetic Engineering, MOE Engineering Research Center of Gene Technology, Shanghai Engineering Research Center of Industrial Microorganisms, School of Life Sciences, Fudan University, Shanghai, 200438, China

    Dongyue Jiao, Yingji Chen, Yalan Wang, Huiru Sun, Qing Shi, Liang Zhang, Xiaying Zhao, Yajuan Liu, Huiying He, Yan Huang, Yao Li & Chenji Wang

  2. Department of Clinical Laboratory, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, China

    Zeheng Lv & Kun Gao

  3. Department of Thyroid and Breast Surgery, Zibo Central Hospital, Zibo, 255036, China

    Chuan Liu & Liang Li

  4. Fudan University Shanghai Cancer Center and Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China

    Pingzhao Zhang

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Contributions

CW conceived the study. DJ, YC, YW, HS, QS, LZ, XZ, YL, HH, ZL, and CL performed the experiments and data analyses. DJ, YC, PZ, KG, YL, YH, LL, and CW analyzed and interpreted the data. CW wrote and revised the manuscript.

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Correspondence to Liang Li or Chenji Wang.

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Jiao, D., Chen, Y., Wang, Y. et al. DCAF12 promotes apoptosis and inhibits NF-κB activation by acting as an endogenous antagonist of IAPs. Oncogene 41, 3000–3010 (2022). https://doi.org/10.1038/s41388-022-02319-5

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