Deciphering the role of the MALT1–RC3H1 axis in regulating GPX4 protein stability

• DOI: 10.1073/pnas.2419625121
• Publication Date: 2024-12-31T18:42:02Z
• Authors: Jun Wang; Long Liao; Beiping Miao; Bo Yang; Botai Li; Xuhui Ma; Annika Fitz; Shanshan Wu; Jia He; Qianqian Zhang; Shuyi Ji; Guangzhi Jin; Jianming Zhang; Ying Cao; Hui Wang; Wenxin Qin; Chong Sun; René Bernards; Cun Wang
• Keywords: Protein Stability

Ferroptosis, a unique form of iron-dependent cell death triggered by lipid peroxidation accumulation, holds great promise for cancer therapy. Despite the crucial role GPX4 in regulating ferroptosis, our understanding protein regulation remains limited. Through FACS-based genome-wide CRISPR screening, we identified MALT1 as regulator protein. Inhibition expression enhances ubiquitination-mediated degradation up-regulating E3 ubiquitin ligase RC3H1. Using both rescue assays and functional genetic demonstrate that pharmacologically targeting triggers ferroptosis liver cells. Moreover, show synergizes with sorafenib or regorafenib to induce across multiple types. These findings elucidate modulatory effects MALT1-RC3H1 axis on stability, revealing molecular mechanism could be exploited