2. Academic Validation
  3. HOIP modulates the stability of GPx4 by linear ubiquitination

HOIP modulates the stability of GPx4 by linear ubiquitination

  • Proc Natl Acad Sci U S A. 2022 Nov;119(44):e2214227119. doi: 10.1073/pnas.2214227119.
Kangyun Dong 1 2,  Ran Wei 1 2,  Taijie Jin 1 2,  Mengmeng Zhang 1,  Jiali Shen 1 2,  Huaijiang Xiang 1 2,  Bing Shan 1,  Junying Yuan 1,  Ying Li 1
Affiliations

Affiliations

  • 1 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 201210 Shanghai, China.
  • 2 University of Chinese Academy of Sciences, 100049 Beijing, China.
PMID: 36279464 DOI: 10.1073/pnas.2214227119
Abstract

LUBAC-mediated linear ubiquitination plays a pivotal role in regulation of cell death and inflammatory pathways. Genetic deficiency in LUBAC components leads to severe immune dysfunction or embryonic lethality. LUBAC has been extensively studied for its role in mediating TNF signaling. However, Tnfr1 knockout is not able to fully rescue the embryonic lethality of LUBAC deficiency, suggesting that LUBAC may modify additional key cellular substrates in promoting cell survival. GPx4 is an important selenoprotein involved in regulating cellular redox homeostasis in defense against lipid peroxidation-mediated cell death known as Ferroptosis. Here we demonstrate that LUBAC deficiency sensitizes to Ferroptosis by promoting GPx4 degradation and downstream lipid peroxidation. LUBAC binds and stabilizes GPx4 by modulating its linear ubiquitination both in normal condition and under oxidative stress. Our findings identify GPx4 as a key substrate of LUBAC and a previously unrecognized role of LUBAC-mediated linear ubiquitination in regulating cellular redox status and cell death.

Keywords

GPx4; LUBAC; TNF; ferroptosis.

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