The Role of Ubiquitination in Regulating Ferroptosis / 生物化学与生物物理进展

Ferroptosis is a novel type of iron-dependent cell death driven by lipid peroxidation. More and more evidence shows that ferroptosis is related to various pathological conditions, such as neurodegenerative diseases, diabetic nephropathy, and cancer. Ferroptosis driven by lipid peroxidation may promote or inhibit the occurrence and development of these diseases. The intracellular antioxidant system plays an important role in resisting ferroptosis by inhibiting lipid peroxidation. The key pathways of ferroptosis include the amino acid metabolism pathway with SLC7A11-GPX4 as the key molecule, the iron metabolism pathway with ferritin or transferrin as the main component, and the lipid metabolism pathway. The occurrence of ferroptosis is regulated by intracellular proteins, which undergo various post-translational modifications, including ubiquitination. The ubiquitin-proteasome system (UPS) is one of the main degradation systems in cells. It catalyzes the ubiquitin molecule to label the protein and then the proteasome recognizes and degrades the target protein. UPS promotes ferroptosis by promoting the degradation of key ferroptosis molecules (such as SLC7A11, GPX4, and GSH) and antioxidant systems (such as NRF2). UPS can also inhibit ferroptosis by promoting the degradation of related molecules in the lipid metabolism pathway (such as ACLS4 and ALOX15). In this review, we summarize the latest research progress of ubiquitination modification in the regulation of ferroptosis, generalize the published studies on the regulation of ferroptosis by E3 ubiquitin ligase and deubiquitination, and sum up the targets of ubiquitin ligase and deubiquitination regulating ferroptosis, which is helpful to identify new prognostic indicators in human diseases and provide potential therapeutic strategies for these diseases.

Cross-talk between c-Jun/Ets1 involved in EB virus-encoded latent membrane protein 1 regulates expression of matrix metalloproteinase-9 in nasopharyngeal carcinoma / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To investigate effect of AP-1 and Ets binding site adjacent to matrix metalloproteinase-9 (MMP-9) promoter on activation of MMP-9 transcription of nasopharyngeal carcinoma cells transfected with EBV-encoded latent membrane protein 1 (LMP1), and to ascertain if cross-talk between c-Jun and Ets1 is involved in LMP1-regulating expression of MMP-9.</p><p><b>METHODS</b>Site-directed mutagenesis technique was used to establish a series of mutants, including MMP-9-CAT-Ets(-540)mt, MMP-9-CAT-AP-1(-533)mt and MMP-9-CAT-AP-1(-533)/Ets(-540)mt. After the mutants were transfected into LMP1-expressing NPC HNE2 cells regulated by Tet-on system (pTet-on-LMP1 HNE2), CAT activity of these mutants were assayed with induction of LMP1. With blockade of c-Jun or Ets1 antisense oligonucleotides, the activity of MMP-9 induced by LMP1 was assayed with gelatin zymography.</p><p><b>RESULTS</b>The CAT activity of MMP-9-Ets(-540)mt-CAT, MMP-9-AP-1(-533)mt-CAT, MMP-9-AP-1(-533)/Ets(-540) mt-CAT decreased significantly compared to MMP-9-CAT wt. After blockade with c-Jun or Ets1 antisense oligonucleotides, activity of MMP-9 induced by LMP1 decreased significantly, especially with combined blockade of c-Jun and Ets1.</p><p><b>CONCLUSION</b>The results suggest that transcription factor AP-1 and Ets play an crucial role in activation of MMP-9 transcription induced by LMP1, and cross-talk between c-Jun/Ets1 is involved in expression of MMP-9 mediated by LMP1.</p>

EB virus encoded latent membrane protein 1 mediated expression of transcription factor Ets-1 in nasopharyngeal carcinoma cells / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To elucidate the expression of tanscription factor Ets-1 mediated by EB virus encoded latent membrane protein 1 (LMP1) in nasopharyngeal carcinoma (NPC) cells.</p><p><b>METHODS</b>LMP1-expressing NPC HNE2 cells regulated by Tet-on system (pTet-on-LMP1 HNE2) were used. Expression of LMP1 and Ets-1 was observed after induction with Doxycycline (Dox). Expression of Ets-1 mRNA and protein was detected by RT-PCR and Western blot, respectively. The phosphorylation level of Ets-1 protein was examined by co-immunoprecipitation. The DNA binding activity of Ets-1 was detected by electrophoretic-mobility shift assay (EMSA).</p><p><b>RESULTS</b>After induction with Dox in pTet-on-LMP1 HNE2 cells, to some extent, the expression of Ets-1 mRNA and protein, its phosphorylation level and DNA binding activity were increased with enhancement of LMP1 expression.</p><p><b>CONCLUSION</b>LMP1 induces transcriptional activation and expression of Ets-1 which may contribute to the development of NPC.</p>