Energy stress promotes P-bodies formation via lysine-63-linked polyubiquitination of HAX1

Wanqi Zhan; Zhiyang Li; Jie Zhang; Yongfeng Liu; Guanglong Liu; Bingsong Li; Rong Shen; Yi Jiang; Wanjing Shang; Shenjia Gao; Han Wu; Ya'nan Wang; Wankun Chen; Zhizhang Wang

doi:10.1038/s44318-024-00120-6

Energy stress promotes P-bodies formation via lysine-63-linked polyubiquitination of HAX1

EMBO J. 2024 May 20. doi: 10.1038/s44318-024-00120-6. Online ahead of print.

Authors

Wanqi Zhan^#^{1

2

3}, Zhiyang Li^#^{1

2

3}, Jie Zhang^#^{4

5}, Yongfeng Liu^#⁶, Guanglong Liu^{1

2

3}, Bingsong Li^{1

7}, Rong Shen^{1

2

3}, Yi Jiang^{4

5}, Wanjing Shang⁸, Shenjia Gao^{4

5}, Han Wu^{4

5}, Ya'nan Wang^{1

2

3}, Wankun Chen^{9

10

11}, Zhizhang Wang^{12

13}

Affiliations

¹ Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
² Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.
³ Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China.
⁴ Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China.
⁵ Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China.
⁶ Radiation Medicine Institute, The First Affiliated Hospital, ZhengZhou University, ZhengZhou, Henan, China.
⁷ Jinfeng Laboratory, Chongqing, China.
⁸ Lymphocyte Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, USA.
⁹ Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China. chen.wankun@zs-hospital.sh.cn.
¹⁰ Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China. chen.wankun@zs-hospital.sh.cn.
¹¹ Department of Anesthesiology, Qingpu Branch of Zhongshan Hospital, Fudan University, Shanghai, China. chen.wankun@zs-hospital.sh.cn.
¹² Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China. wangzz89@smu.edu.cn.
¹³ Jinfeng Laboratory, Chongqing, China. wangzz89@smu.edu.cn.

^# Contributed equally.

PMID: 38769438
DOI: 10.1038/s44318-024-00120-6

Abstract

Energy stress, characterized by the reduction of intracellular ATP, has been implicated in various diseases, including cancer. Here, we show that energy stress promotes the formation of P-bodies in a ubiquitin-dependent manner. Upon ATP depletion, the E3 ubiquitin ligase TRIM23 catalyzes lysine-63 (K63)-linked polyubiquitination of HCLS1-associated protein X-1 (HAX1). HAX1 ubiquitination triggers its liquid‒liquid phase separation (LLPS) and contributes to P-bodies assembly induced by energy stress. Ubiquitinated HAX1 also interacts with the essential P-body proteins, DDX6 and LSM14A, promoting their condensation. Moreover, we find that this TRIM23/HAX1 pathway is critical for the inhibition of global protein synthesis under energy stress conditions. Furthermore, high HAX1 ubiquitination, and increased cytoplasmic localization of TRIM23 along with elevated HAX1 levels, promotes colorectal cancer (CRC)-cell proliferation and correlates with poor prognosis in CRC patients. Our data not only elucidate a ubiquitination-dependent LLPS mechanism in RNP granules induced by energy stress but also propose a promising target for CRC therapy.

Keywords: Energy Stress; HAX1; P-bodies; TRIM23; Translation Inhibition.

Abstract

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