Ubiquitin ligase E3 HUWE1/MULE targets transferrin receptor for degradation and suppresses ferroptosis in acute liver injury

Abstract

Hepatic ischemia followed by reperfusion (I/R), a major clinical problem during liver surgical procedures, can induce liver injury with severe cell death including ferroptosis which is characterized by iron-dependent accumulation of lipid peroxidation. The HECT domain-containing ubiquitin E3 ligase HUWE1 (also known as MULE) was initially shown to promote apoptosis. However, our preliminary study demonstrates that high expression of HUWE1 in the liver donors corelates with less injury and better hepatic function after liver transplantation in patients. Thus, we investigate the role of HUWE1 in acute liver injury, and identify HUWE1 as a negative ferroptosis modulator through transferrin receptor 1(TfR1). Deficiency of Huwe1 in mice hepatocytes (HKO) exacerbated I/ R and CCl 4 -induced liver injury with more ferroptosis occurrence. Moreover, Suppression of Huwe1 remarkably enhances cellular sensitivity to ferroptosis in primary hepatocytes and mouse embryonic fibroblasts. Mechanistically, HUWE1 specifically targets TfR1 for ubiquitination and proteasomal degradation, thereby regulates iron metabolism. Importantly, chemical and genetic inhibition of TfR1 dramatically diminishes the ferroptotic cell death in Huwe1 KO cells and Huwe1 HKO mice. Therefore, HUWE1 is a potential protective factor to antagonize both aberrant iron accumulation and ferroptosis thereby mitigating acute liver injury. These findings may provide clinical implications for patients with the high-expression Huwe1 alleles.

The m6A reader YTHDF3-mediated PRDX3 translation alleviates liver fibrosis

“…For in vivo PRDX3 knockdown, PRDX3 shRNA was driven by the U6 promoter and packaged into AAV9 [ 45 ]. In addition, PRDX3-Flag or YTHDF3-Myc plasmids were driven by the pGFAP promoter and packaged into AAV9 for the overexpression of PRDX3 or YTHDF3 in HSCs.…”

The giant E3 ligase HUWE1 is linked to tumorigenesis, spermatogenesis, intellectual disability, and inflammatory diseases

“…In addition, our study proved the inhibitory activity of BI8622 and BI8626 against HUWE1 in the inflammasome activation pathway and the potential therapeutic applications of BI8622 and BI8626 in treating inflammatory diseases (Guo et al, 2020a). Very recently, HUWE1 was demonstrated to target transferrin receptor 1 (TfR1) for degradation and inhibit ferroptosis in hepatocytes (Wu et al, 2022). Despite the significant advances achieved in identifying HUWE1 targets, our current understanding of HUWE1 activity regulation, particularly the temporal and spatial modulation of HUWE1 activation, is limited.…”

TRIM7 modulates NCOA4-mediated ferritinophagy and ferroptosis in glioblastoma cells

“…Changes in iron homeostasis are identified as a key metabolic hallmark of human cancer, and iron metabolic reprogramming and dysfunction have also been shown to occur in human glioblastoma [ 19 , 56 ]. TF is an important iron-transport protein and mediates majority of the cellular iron uptake through binding to the cell-surface TFR, and then the TF/TFR complex is internalized by receptor-mediated endocytosis and releases iron into the cytosol [ 57 ]. However, in the present study, neither TF nor TFR expression was affected by TRIM7 silence in human glioblastoma cells.…”