American Association for Cancer Research

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Supplementary Table3 from USP48 Stabilizes Gasdermin E to Promote Pyroptosis in Cancer

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posted on 2023-04-04, 12:06 authored by Yidan Ren, Maoxiao Feng, Xiaodong Hao, Xiaoyan Liu, Juan Li, Peilong Li, Jie Gao, Qiuchen Qi, Lutao Du, Chuanxin Wang, Qin Wang, Yunshan Wang

Supplementary Table3


National Natural Science Foundation of China (NSFC)

Key Technology Research and Development Program of Shandong (Key Technology R&D Program of Shandong Province)

Taishan Scholar Project of Shandong Province

Natural Science Foundation of Shandong Province (Natural Science Foundation of Shandong)

Qilu Young Scholars Program of Shandong University



Pyroptosis is a type of programmed cell death characterized by the activation of inflammatory caspases and the cleavage of gasdermin proteins. Pyroptosis can suppress tumor development and induce antitumor immunity, and activating pyroptosis is a potential treatment strategy for cancer. To uncover approaches to harness the anticancer effects of pyroptosis, we aimed to identify regulators of pyroptosis in cancer. A CRISPR-Cas9 screen identified that loss of USP48, a deubiquitinating enzyme, significantly inhibited cell pyroptosis. USP48 promoted pyroptosis by stabilizing gasdermin E (GSDME). USP48 bound GSDME and removed K48-linked ubiquitination at positions K120 and K189. Clinical tissue testing confirmed that the expression of USP48 positively correlated with GSDME and pyroptosis-related factors. Single-cell sequencing showed that the functions of T cells and tumor-associated macrophages in the tumor microenvironment were inhibited after USP48 knockout. Finally, overexpression of USP48 enhanced the therapeutic efficacy of programmed cell death protein 1 inhibitors in tumors in mouse models. Together, these findings define a pyroptosis regulation pathway and indicate that pharmacologic activation of USP48 may provide an effective strategy to sensitize cancer cells to pyroptosis and improve response to immunotherapy. USP48 promotes pyroptosis by deubiquitinating GSDME and enhances antitumor immunity, indicating that increasing USP48 activity may be a future therapeutic strategy for treating cancer.

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