O-GlcNAcylation regulates the stability of transferrin receptor (TFRC) to control the ferroptosis in hepatocellular carcinoma cells
Xunyu Zhou,
Yida Wang,
Xiaoyu Li,
Jing Zhou,
Wanyi Yang,
Xin Wang,
Sitong Jiao,
Weibo Zuo,
Ziming You,
Wantao Ying,
Chuanfang Wu,
Jinku Bao
Affiliations
Xunyu Zhou
School of Life Sciences, Sichuan University, Chengdu, 610041, China
Yida Wang
School of Life Sciences, Sichuan University, Chengdu, 610041, China
Xiaoyu Li
State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
Jing Zhou
West China Hospital, Sichuan University, Chengdu, 610041, China
Wanyi Yang
School of Life Sciences, Sichuan University, Chengdu, 610041, China
Xin Wang
School of Life Sciences, Sichuan University, Chengdu, 610041, China
Sitong Jiao
School of Life Sciences, Sichuan University, Chengdu, 610041, China
Weibo Zuo
School of Life Sciences, Sichuan University, Chengdu, 610041, China
Ziming You
School of Life Sciences, Sichuan University, Chengdu, 610041, China
Wantao Ying
State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China; Corresponding author. State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Life Science Avenue No.38, Beijing, 102206, China.
Chuanfang Wu
School of Life Sciences, Sichuan University, Chengdu, 610041, China; Corresponding author. School of Life Sciences, Sichuan University, First Ring Road No. 24, Chengdu, 610041, China.
Jinku Bao
School of Life Sciences, Sichuan University, Chengdu, 610041, China; Corresponding author. School of Life Sciences, Sichuan University, First Ring Road No. 24, Chengdu, 610041, China.
Ferroptosis is an iron-dependent programmed cell death (PCD) enforced by lipid peroxidation accumulation. Transferrin receptor (TFRC), one of the signature proteins of ferroptosis, is abundantly expressed in hepatocellular carcinoma (HCC). However, post-translational modification (PTM) of TFRC and the underlying mechanisms for ferroptosis regulation remain less understood. In this study, we found that TFRC undergoes O-GlcNAcylation, influencing Erastin-induced ferroptosis sensitivity in hepatocytes. Further mechanistic studies found that Erastin can trigger de-O-GlcNAcylation of TFRC at serine 687 (Ser687), which diminishes the binding of ubiquitin E3 ligase membrane-associated RING-CH8 (MARCH8) and decreases polyubiquitination on lysine 665 (Lys665), thereby enhancing TFRC stability that favors labile iron accumulation. Therefore, our findings report O-GlcNAcylation on an important regulatory protein of ferroptosis and reveal an intriguing mechanism by which HCC ferroptosis is controlled by an iron metabolism pathway.
