Associate Researcher Wang Chenji of Fudan University and Professor Li Liang of Zibo Central Hospital jointly published a paper titled " DCAF12 promotes apoptosis and inhibits NF-κB activation by acting as an endogenous antagonist of " Oncogene Magazine on April 22 , 2022 .
The latest research results of IAPs ” .
Apoptosis or programmed cell death is an evolutionarily conserved process that is required for normal development, homeostasis and integrity of multicellular organisms
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In normal cells, there is a good regulatory balance between pro-apoptotic proteins and anti-apoptotic proteins, and they work together to regulate apoptosis
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Tumor cells inhibit apoptosis by upregulating the activity of anti-apoptotic proteins, which ultimately leads to phenotypes such as malignant proliferation and drug resistance of tumors
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IAP (Inhibitor of apoptosis) is a highly conserved endogenous inhibitor of apoptosis protein, and its anti-apoptotic function depends on the interaction of the BIR domain with Caspase ( Caspase ) family proteins
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The dysfunction of IAP family proteins is usually closely related to pathological processes such as inflammation and tumorigenesis .
When cells receive apoptotic signals, they activate a class of proteins called IAP antagonists, which bind to IAPs , release the inhibitory effect of IAPs , and promote Caspase activation .
The reported IAP antagonists include SMAC , HtrA2 and XAF1 .
DCAF12 is a substrate-recognition subunit of the Cullin 4 ( CUL4 ) E3 ubiquitin ligase complex
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The CRL4-DCAF12 complex can bind and mediate the ubiquitination degradation of multiple substrates such as MAGEA3 and YAP .
A recent screening of Drosophila apoptosis-related genes found that the Drosophila homologous protein dcaf12 is a pro-apoptotic factor ( Dev Biol.
2016;413:50-9.
), but the specific molecular mechanism has not yet been elucidated.
It is also unknown whether DCAF12 performs dcaf12 - like pro-apoptotic functions in cells .
In this study, the team reported that human DCAF12 binds multiple IAP family proteins , including XIAP , cIAP1 , cIAP2 and BRUCE , by recognizing the BIR domain in IAPs .
DCAF12
The pro-apoptotic function of IAP depends on its ability to bind to IAPs , but does not affect the protein stability of IAPs .
When cells initiate apoptosis, DCAF12 translocates from the nucleus to the cytoplasm, blocking the interaction between XIAP and pro-apoptotic Caspases 3/7/9 , promoting the activation of Caspase 3/7/9 and the execution of apoptosis .
In addition, this study also found that DCAF12 inhibited the activation of NF-κB signaling pathway in an IAPs binding -dependent manner .
DCAF12 is downregulated in a variety of tumors, and its deletion enhances many phenotypes of malignant transformation such as tumor cell proliferation and invasion .
These results suggest that the pro-apoptotic function of DCAF12 is independent of the function of the substrate-recognition subunit of CRL4 and is an evolutionarily conserved novel IAP antagonist .
Molecular mechanism of DCAF12- dependent regulation of apoptosis by IAPs
Jiao Dongyue and Chen Yingji, doctoral students of the School of Life Sciences of Fudan University, are the co-first authors of the paper, and Associate Researcher Wang Chenji and Professor Li Liang of Zibo Central Hospital are the co-corresponding authors of the paper
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