The RING type ubiquitin ligase (E3), XBAT35.2, positively regulates FLS2-mediated plant immunity against bacterial pathogens by modifying the ESCRT-I subunits VPS28-2 and VPS37-1 with distinct ubiqui...

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Nature Structural & Molecular Biology, Published online: 10 September 2026; doi:10.1038/s41594-026-01884-7Wang et al. show that the UT3 domain of Ufd1 binds to and unfolds K48-linked polyubiquitin chains without ATP. Simultaneous binding of two ubiquitins to UT3 is key to overcome the energy barrier. This ubiquitin unfolding is critical for Cdc48/p97’s function.

Nature Structural & Molecular Biology, Published online: 10 September 2026; doi:10.1038/s41594-026-01884-7Wang et al. show that the UT3 domain of Ufd1 binds to and unfolds K48-linked polyubiquitin chains without ATP. Simultaneous binding of two ubiquitins to UT3 is key to overcome the energy barrier. This ubiquitin unfolding is critical for Cdc48/p97’s function.

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Read the full paper: Oncogenic USP3 promotes hepatocellular carcinoma progression via K11/K48-specific deubiquitination and stabilization of YAP

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YouTube video by Sparkin

Radioresistance arises partly from tumor cells evading cuproptosis via unknown defenses. This study reveals that the PRMT5-VPS34 axis acts as a radiation-activated anticuproptotic mechanism: PRMT5 methylates VPS34 at Arg174, recruiting USP10 to remove K48-linked ubiquitination and prevent degradation. Stabilized VPS34 lowers copper levels by degrading importer SLC31A1 and relocating exporter ATP7A, conferring adaptive radioresistance. Targeting this axis unleashes copper cytotoxicity and sensitizes refractory tumors to radiotherapy. ABSTRACT Targeting cuproptosis for cancer therapy is hindered by an incomplete understanding of the intrinsic defense networks through which tumor cells mobilize to evade this fate, particularly under therapeutic stress such as radiotherapy. Here, we identify VPS34-mediated copper homeostasis as a critical anticuproptotic process through a genome-wide CRISPR activation screen. PRMT5 directly methylated VPS34 at Arg174 and inhibited K48-linked polyubiquitination and proteasomal degradation of VPS34 by recruiting the deubiquitinase USP10. This stabilization increased the cuproptotic defense of tumor cells by promoting autophagic degradation of the copper importer SLC31A1 and plasma membrane translocation of the exporter ATP7A, thereby reducing the intracellular copper load. Functional analysis and clinical correlation revealed that the PRMT5-VPS34 axis is robustly activated by radiation stress and is necessary for adaptive radioresistance. The inhibition of PRMT5 or VPS34 expression suppressed tumor growth and enhanced the sensitivity of tumors to radiotherapy by unleashing latent copper cytotoxicity both in vitro and in vivo. Together, our findings identify the PRMT5-VPS34 axis as a therapeutic target for sensitizing refractory cancers to radiotherapy.

YouTube video by Jim Acosta