bims-cutpro 2026-02-01 papers

bims-cutpro

Biomed News

on Cullin targeted protein degradation

Issue of 2026–02–01
eight papers selected by
James M. Krieger, Francis Crick Institute

Targeting the Ubiquitin-Proteasome System in Atrial Fibrillation: Mechanistic Insights and Translational Perspectives.
The dual face of reprogrammed proteostasis in cancer and its epigenetic regulation: A survival option and a therapeutic opportunity.
TRIM9 and TRIM26 Interact with UBQLN2P497H to Modulate Its Proteasomal Degradation.
Mebendazole inhibits PELI3-mediated ubiquitination of TRADD in non-small cell lung cancer cells.
Tubby-like protein TaTLP5 enhances stripe rust resistance in wheat by regulating TaCAT1 protein degradation.
Radiation-induced nuclear translocation of NPRL2 hijacks E3 ubiquitin ligases to enhance DNA repair via the AMPK/WDR24 axis, contributing to CRC radioresistance.
miR-381-3p suppresses pterygium progression by regulating HACE1/TRIP12-mediated ubiquitin-degradation of MCPIP1.
Lock, relax, load, and shoot: a molecular perspective on Nedd4 regulation.

Curr Issues Mol Biol. 2025 Dec 29. pii: 46. [Epub ahead of print]48(1):

Targeting the Ubiquitin-Proteasome System in Atrial Fibrillation: Mechanistic Insights and Translational Perspectives.

Runze Huang, Zhipeng Pu, Zhangrong Chen.

  Atrial fibrillation (AF) is the most common sustained arrhythmia, and its initiation and progression involve multiple mechanisms, including electrical remodeling, structural remodeling, inflammatory responses, and oxidative stress. In recent years, the ubiquitin-proteasome system (UPS), a central pathway for maintaining intracellular protein homeostasis, has attracted increasing attention in the pathogenesis of AF. By regulating the degradation and expression of ion channel proteins, Ca2+-handling molecules, and pro-fibrotic signaling factors, the UPS plays a pivotal role in key pathological processes such as electrical and structural remodeling. Several E3 ubiquitin ligases (e.g., NEDD4-1/2, MuRF1, WWP1/2, TRAF6), deubiquitinating enzymes (e.g., JOSD2), and immunoproteasome subunits (e.g., β5i) have been shown to exert critical regulatory effects on atrial electrophysiological disturbances, interstitial remodeling, and inflammation. This review provides a comprehensive summary of the regulatory mechanisms of the UPS in AF-associated pathological processes, outlines potential therapeutic targets, and highlights current intervention strategies, including proteasome inhibitors, selective E3 ligase modulators, and natural compounds. Moreover, we discuss the latest advances and future perspectives regarding the application of UPS-based interventions in AF, aiming to provide theoretical foundations and research insights for the mechanistic exploration and innovative therapeutic development of AF.

Keywords:  atrial fibrillation; biomarker; cardiovascular disease; therapeutic target; ubiquitin–proteasome system

DOI:  https://doi.org/10.3390/cimb48010046
Biochim Biophys Acta Mol Cell Res. 2026 Jan 23. pii: S0167-4889(26)00012-1. [Epub ahead of print]1873(3): 120116

The dual face of reprogrammed proteostasis in cancer and its epigenetic regulation: A survival option and a therapeutic opportunity.

Mara Cirone.

  Proteostasis is essential for cellular homeostasis and is maintained through an integrated network encompassing the unfolded protein response (UPR), molecular chaperones such as heat shock proteins (HSPs), and degradative systems including the ubiquitin-proteasome and autophagy-lysosomal pathways. In cancer, microenvironmental stresses such as hypoxia, nutrient deprivation, and oxidative imbalance impose a persistent proteotoxic burden, driving a context-dependent rewiring of these pathways that supports tumor survival, plasticity, and progression. Increasing evidence indicates that the functional outcomes of proteostasis responses, whether adaptive or cytotoxic, are determined by specific molecular cues, including the intensity and duration of stress, pathway crosstalk, and cell-intrinsic oncogenic alterations. Epigenetic mechanisms, comprising DNA methylation, histone modifications, and non-coding RNAs, further fine-tune these proteostatic programs by modulating the expression and activity of key regulators, thereby contributing to drug resistance but also generating cancer-selective vulnerabilities. This review provides a structured and mechanistic overview of how UPR, chaperone networks, and protein degradation pathways are remodeled in cancer and examines the epigenetic determinants that shape their adaptive behavior. Finally, we discuss emerging translational opportunities arising from the dual role of proteostasis in cancer, highlighting therapeutic strategies that exploit the dynamic interplay between proteostatic and epigenetic regulation.

Keywords:  Autophagy; Cancer; Epigenetics; HSPs; UPR; UPS

DOI:  https://doi.org/10.1016/j.bbamcr.2026.120116
ACS Chem Biol. 2026 Jan 25.

TRIM9 and TRIM26 Interact with UBQLN2P497H to Modulate Its Proteasomal Degradation.

Xingyuan Chen, Zhongwen Cao, Xiaochen Liang, Ting Zhao, Yinsheng Wang.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron loss. ALS-linked mutations in UBQLN2 promote protein aggregation and disrupt proteostasis, yet the mutation-specific protein interactomes and their functional relevance remain poorly defined. We employed APEX2 proximity labeling, together with affinity enrichment of biotinylated peptides and LC-MS/MS analysis, to profile the interactomes of wild-type UBQLN2 and two ALS-linked variants, UBQLN2P497H and UBQLN2P497S. We identified 785 unique biotinylated proteins, many of which exhibit augmented enrichment in the proximity proteomes of the two mutants over wild-type UBQLN2. Notably, the E3 ubiquitin ligases TRIM9 and TRIM26 were selectively enriched in the proximity proteome of UBQLN2P497H, which we validated by coimmunoprecipitation followed by Western blot analysis. Fractionation analysis revealed coaccumulation of TRIM9 and TRIM26 with UBQLN2P497H in the insoluble fraction, consistent with its heightened aggregation propensity. Treatment of UBQLN2P497H-expressing cells with a proteasomal inhibitor led to elevated accumulation of a C-terminal UBQLN2 fragment that is absent in cells expressing wild-type UBQLN2 or its P497S mutant. Individual knockdown of TRIM9 and TRIM26 significantly increased the abundance of the fragment, establishing UBQLN2P497H as a substrate for TRIM9- and TRIM26-mediated ubiquitinylation and subsequent proteasomal degradation. These findings nominate TRIM9 and TRIM26 as specific interactors of UBQLN2P497H and as regulators of a previously underexplored C-terminal UBQLN2 fragment, suggesting that impaired clearance of this species may contribute to ALS pathogenesis.

DOI: https://doi.org/10.1021/acschembio.5c00911
Front Oncol. 2025 ;15 1728170

Mebendazole inhibits PELI3-mediated ubiquitination of TRADD in non-small cell lung cancer cells.

Fannian Li, Xiaoning Li, Haitao Li, Shuai Li, Yanchao Liu, Xianhua Bai, Tianjie Qi, Xiumin Zhao, Yuzheng He.

   Introduction: Tumor necrosis factor receptor 1-associated death domain protein (TRADD) can trigger proapoptotic autophagy in non-small cell lung cancer (NSCLC). While the potential ubiquitin-protein ligase (E3) against TRADD is not well deciphered.
Methods: UbiBrowser was used to predict the potential E3 ubiquitin ligase to bind with TRADD. Co-immunoprecipitation was performed in HEK293T cells co-transfected with Myc-PELI3, Flag-TRADD, or HA-Ub plasmids. Increasing doses of Myc-PELI3 were transfected into HCC827 and A549 cells, and the relative expression of TRADD was detected. Cycloheximide chase assay was performed in A549 cells transfected with Myc-PELI3 plasmids, and the stability of TRADD was revealed. CCK-8 assay was performed in A549 and HCC827 cells incubated with increasing doses of Mebendazole. The expression of TRADD and PELI3 after Mebendazole incubation was assayed with Western Blot and RT-PCR. The potential E3 ubiquitin ligase of PELI3 was predicted by the UbiBrowser platform, and the binding of PELI3 with TRADD was testified in HEK293T cells co-transfected with Myc-PELI3 and Flag-TRADD plasmids.
Results: PELI3 overexpression diminished the relative protein expression of TRADD, while not affecting the relative mRNA expression in both A549 and HCC827 cells. Cycloheximide assay and following HA-Ub detection demonstrated that PELI3 decreased the protein stability of TRADD by inducing polyubiquitination. Mebendazole inhibited the viability of HCC827 and A549 cells with diminished expression of PELI3 and increased expression of TRADD.
Conclusions: PELI3 can function as an E3 ubiquitin ligase to ubiquitinate TRADD, and Mebendazole might be a promising drug to affect PELI3 expression in NSCLC.

Keywords:  E3 ubiquitin ligase; PELI3; TRADD; mebendazole; non-small cell lung cancer

DOI:  https://doi.org/10.3389/fonc.2025.1728170
New Phytol. 2026 Jan 28.

Tubby-like protein TaTLP5 enhances stripe rust resistance in wheat by regulating TaCAT1 protein degradation.

Yanqin Zhang, Longhui Yu, Yi Lin, Shuangyuan Guo, Haoshan Liu, Xiaojie Wang, Zhensheng Kang, Xinmei Zhang.

  Although tubby-like proteins (TLPs) are evolutionarily conserved across eukaryotes, their roles in orchestrating plant immune responses, particularly against obligate biotrophic pathogens, remain poorly defined. In this study, we found that TaTLP5, a member of the tubby-like F-box gene family, is rapidly upregulated following Puccinia striiformis f. sp. tritici (Pst) infection. Silencing TaTLP5 in wheat enhances susceptibility to Pst, whereas its overexpression confers resistance by promoting reactive oxygen species (ROS) accumulation. In addition, the molecular interaction mechanism underlying TaTLP5-mediated wheat disease resistance has been elucidated. The results showed that TaTLP5 forms an SKP1-Cullin1-F-box (SCF)-type E3 ubiquitin ligase complex with TaSKP1 (S-phase kinase-associated protein 1) and TaCullin1. Notably, this complex mediates the ubiquitination and degradation of TaCAT1 (Catalase1), a key susceptibility factor in wheat. This ubiquitination-dependent degradation of TaCAT1 elevates ROS accumulation, thereby enhancing wheat resistance against Pst. Our findings revealed a conserved regulatory module by which the TaTLP5-TaSKP1-TaCullin complex modulates ROS-dependent immunity via ubiquitination-mediated degradation of TaCAT1 during wheat-Pst interactions. These mechanistic insights highlight potential actionable targets for the rational breeding of disease-resistant crop varieties.

Keywords:  Puccinia striiformis f. sp. tritici; catalase; reactive oxygen species; tubby‐like protein; ubiquitination; wheat

DOI:  https://doi.org/10.1111/nph.70956
Acta Pharm Sin B. 2026 Jan;16(1): 252-269

Radiation-induced nuclear translocation of NPRL2 hijacks E3 ubiquitin ligases to enhance DNA repair via the AMPK/WDR24 axis, contributing to CRC radioresistance.

Xuecen Wang, Yuxuan Zhao, Xingli Yang, Tingyu Liu, Weilin Zhou, Shaoqing Niu, Meng Jin, Yong Chen, Ran-Yi Liu, Yong Bao, Xin Yue.

  Radiotherapy resistance remains a major clinical challenge in colorectal cancer (CRC) treatment. Our study reveals that the regulation of nuclear E3 ubiquitin ligase maintains K48-ubiquitin levels that correlate with CRC radiotherapy sensitivity. We identify NPRL2 as the central mediator of this process. Following radiation, NPRL2 rapidly translocates to the nucleus, where it directly binds to the catalytic domains of key E3 ubiquitin ligases, including HERC2 and RNF8, and functionally inactivates them. This NPRL2-mediated inhibition of E3 ligase activity prevents the degradation of critical DNA repair proteins. Importantly, clinical analyses demonstrate that nuclear NPRL2 plays a role in sustaining radioresistance. Mechanistic investigations reveal that radiation-induced AMPK activation initiates this process by phosphorylating WDR24, which promotes NPRL2 dissociation from the GATOR1 complex and facilitates its nuclear translocation. Therapeutic targeting through AMPK inhibition effectively blocks NPRL2 nuclear accumulation, leading to impaired DNA damage repair and significant radiosensitization of CRC cells in both in vitro and in vivo models. These findings not only elucidate the AMPK/WDR24/NPRL2 signaling axis as a fundamental regulator of DNA repair machinery in CRC, but also provide compelling evidence for its potential as a novel therapeutic target to overcome radioresistance and improve radiotherapy efficacy in CRC patients.

Keywords:  AMPK/WDR24 axis; CRC radioresistance; DNA repair; E3 ubiquitin ligases; NPRL2; Nuclear translocation; Radiation induction; Therapeutic target

DOI:  https://doi.org/10.1016/j.apsb.2025.10.039
In Vitro Cell Dev Biol Anim. 2026 Jan 29.

miR-381-3p suppresses pterygium progression by regulating HACE1/TRIP12-mediated ubiquitin-degradation of MCPIP1.

Yubing Zhao, Hao Ji, Yang He, Weijia Zhang, Yanze Xu, Yuru Yin, Yan Du, Dandan Zhao.

  Pterygium syndrome is a common eye disease that often leads to vision loss and even blindness. There is increasing evidence that miRNAs play a key role in the progression of pterygium, but the function of miR-381-3p in pterygium has not been studied. Therefore, this study aimed to investigate the effect of miR-381-3p on the progression of pterygium and to elucidate its potential molecular mechanisms. Human pterygium fibroblasts (HPFs) were isolated from clinical pterygium tissues. The expression of key genes and proteins was detected via RT-qPCR and western blotting. Cell proliferation was detected by CCK-8 and scratch assay, while cell invasion was examined by Transwell assay. Protein interactions were investigated by coimmunoprecipitation. First, we found that the expression level of miR-381-3p was significantly reduced in pterygium tissues. Second, we found that the overexpression of miR-381-3p in HPFs inhibited the proliferation, migration, and invasion abilities of HPFs while inducing cell apoptosis. In addition, in pterygium tissue, the expression of MCPIP1 was downregulated, and the expression of HACE1 and TRIP12 was upregulated. Importantly, MCPIP1 interference partially attenuated the positive effects of miR-381-3p overexpression described above, and miR-381-3p could target HACE1, while HACE1 could bind to TRIP12. Mechanistic studies revealed that miR-381-3p inhibited the binding of HACE1 to TRIP12 through the inhibition of HACE1 expression, thereby inhibiting the ubiquitination and degradation of MCPIP1 and improving the progression of pterygium. Our study highlights the powerful potential of miR-381-3p in improving the progression of pterygium, laying the foundation for the development of new intervention targets for related diseases.

Keywords:  HACE1/TRIP12; MCPIP1; MiR-381-3p; Pterygium; Ubiquitination

DOI:  https://doi.org/10.1007/s11626-025-01119-x
FEBS J. 2026 Jan 29.

Lock, relax, load, and shoot: a molecular perspective on Nedd4 regulation.

Masa Janosev, Tomas Obsil, Veronika Obsilova.

  The Nedd4 subfamily of HECT E3 ligases is a ubiquitous group of 10 enzymes that share the same domain structure, consisting of a C2 domain, several WW domains and a catalytic HECT domain. Over the past decade, significant progress has been made in characterizing the molecular details of their activity and regulation. Studies have shown that, in the inactive state, the HECT domain is shielded by its N-terminal domains, thereby blocking access to the active site. The catalytic functions of Nedd4 enzymes include accepting ubiquitin molecules from ubiquitin-conjugating enzymes, transferring them to substrates, and generating diverse polyubiquitin chains. The modulation of Nedd4 enzyme activity involves mechanisms that facilitate enzymatic activation, relay binding to components of the enzymatic cascade, and enable (auto)ubiquitination. This minireview provides a comprehensive overview of the structural features distinguishing the inactive and active conformations in this group of E3 ligases, while underscoring the need for further research necessary to develop pharmaceutical solutions targeting pathological conditions rooted in Nedd4 dysfunction.

Keywords:  HECT; Nedd4; enzymatic conformations; intramolecular binding; ubiquitination

DOI:  https://doi.org/10.1111/febs.70424