SQSTM1/p62 is a master regulator of the autophagic and ubiquitination pathways of protein degradation and the antioxidant response. p62 functions in these pathways via reversible assembly and sequestration of additional factors into cytoplasmic phase-separated structures termed p62 bodies. The physiological roles of p62 in these various pathways depend on numerous mechanisms for regulating p62 body formation and dynamics that are incompletely understood. Here, we identify a new mechanism for regulation of p62 oligomerization and incorporation into p62 bodies by SHKBP1, a cullin-3 E3 ubiquitin ligase adaptor, that is independent of its potential functions in ubiquitination. We map an SHKBP1-p62 protein-protein interaction outside of p62 bodies that limits p62 assembly into p62 bodies and affects the antioxidant response involving sequestration of Keap1 and nuclear translocation of Nrf2. These studies provide a non-ubiquitination-based mechanism for an E3 ligase adaptor in regulating p62 body formation and cellular responses to oxidative stress.

Development of the fluorescence polarization-based competition assay for the E3 ligase GID4.

Discovery of KRAS-G12D degraders via exploration of various E3 ligases.

TRIM7 negatively regulates CMPK2 suppressing inflammation and apoptosis in renal ischemia-reperfusion injury.

Ubiquitin regulatory code: unraveling tumor cell ferroptosis.

RNA interference (RNAi) is a major antiviral defense in fungi, yet the regulatory mechanisms governing this pathway remain incompletely characterized. In this study, we identified GzC2H056 as a host factor required for the induction of FgDICER-2 and FgAGO-1 in Fusarium graminearum during infection by the Fusarium graminearum virus 2 (FgV2). GzC2H056 expression is transcriptionally induced upon FgV2 infection and exhibits both RNA-binding and E3 ubiquitin ligase activity in vitro. Fluorescence tagging showed that GzC2H056 co-localizes with poly(A)-binding protein 1 and 5'-to-3' exoribonuclease 1, which are markers of stress granules and P-bodies, respectively. RNA-sequencing analysis further revealed that GzC2H056 regulates the expression of genes involved in RNA metabolism and transcription factors linked to RNAi induction. Together, these findings identify GzC2H056 as a regulator of antiviral RNAi in fungi, suggesting that RNA granule-associated mechanisms contribute to fungal defense against mycoviruses.

SCF-FBXO31 E3 ubiquitin ligase in cancer: Molecular insights and clinical implications.

Tripartite motif-containing 37 (TRIM37) is an E3 ubiquitin ligase that epigenetically silences tumor suppressors in DNA repair, regulates polo-like kinase 4, promotes chromosomal instability, and functions as an oncogenic driver in breast cancer (BC). Preclinical studies have implicated TRIM37 in chemotherapy resistance, particularly in triple-negative breast cancer (TNBC), and TRIM37-targeted therapy is in development. However, TRIM37 has not been fully investigated in patients with BC, so its prognostic and therapeutic significance remains unclear. TRIM37 expression was analyzed in 6558 patients across four large, independent cohorts with transcriptome data (METABRIC, TCGA, SCAN-B, and GSE25066). TRIM37 expression was higher in estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative BC than in TNBC, and it was associated with worse disease-free, disease-specific, and overall survival in ER-positive/HER2-negative BC but not in TNBC. TRIM37 expression was significantly associated with DNA repair pathways, homologous recombination deficiency, mutation rates, and enhanced cancer cell proliferation, as evidenced by Nottingham histological grade, Ki67 expression, and gene set enrichment analysis. TRIM37 expression correlated with reduced immune activity, lower cytolytic activity, and decreased response to neoadjuvant chemotherapy in ER-positive/HER2-negative BC, whereas TRIM37-high TNBC displayed higher neoantigen burden and improved chemotherapy response. TRIM37 expression is associated with increased cell proliferation, regardless of subtype; however, it is strongly associated with reduced immune activity, worse response to chemotherapy, and poor prognosis in ER-positive/HER2-negative BC, whereas it was associated with better response to chemotherapy and no relationship with survival in TNBC. Our results provide critical insights into the clinical application of TRIM37-targeted therapies.

Hypoxia-inducible factor-1α in cardiovascular disease, mechanistic insights, pathophysiological roles, and therapeutic targeting strategies.

Silencing the ubiquitin-protein ligases gene (E3-UBR7) alters acquisition, replication, and transmission of groundnut bud necrosis virus by Thrips palmi.

Proteolysis-targeting chimeras (PROTACs) and molecular glues promote targeted protein degradation by recruiting an E3 ligase to proteins of interest (POIs). An accurate 3D structure of the ternary complex formed by E3 ligase, ligand, and POI is central to the rational design of degraders. Elucidating this structure with crystallography or cryo-EM can be challenging due to conformational flexibility, dynamic protein-protein interactions, and high-dimensional binding landscapes. To facilitate structure-based design in the absence of an experimental structure, computational approaches have been proposed: (i) multistep methods involving traditional docking pipelines, and (ii) single-step methods with deep learning models to directly predict the complex structure. Multistep methods are limited by sampling complexity, accurate input structures, scoring accuracy, and computational cost, while single-step methods are faster but are constrained by training-data scarcity. Here, we examine recent advances and emerging tools in modeling ternary complexes, critically discuss their predictive power and limitations, and highlight remaining challenges.

The field of targeted protein degradation (TPD) has emerged as a novel therapeutic approach based on event-driven pharmacology, rather than on continuous occupancy or inhibition of a target. Proteolysis-targeting chimeras (PROTACs) are one of the main TPD modalities, enabling a protein of interest (POI) to be brought into proximity with a ubiquitin ligase, which facilitates ubiquitination of the target protein, leading to its degradation. The design of PROTACs involves the development of heterobifunctional compounds composed of three parts: a POI ligand, a linker, and an E3 ligase ligand. To date, PROTAC technology has been applied to degrade a wide range of targets, with particular interest in previously "undruggable" targets, such as transcription factors. In this context, oligonucleotides have emerged as potential POI binders for transcription factors, since these targets naturally bind to DNA to modulate gene expression. This has led to the development of oligonucleotide-based degraders. Moreover, the role of oligonucleotides has expanded beyond their use as POI ligands. Several strategies have been explored to overcome inherent challenges such as poor stability and limited drug delivery. Currently, novel approaches also demonstrate the potential of nucleotides to function as linkers, where they can exert control over the spatial orientation between the POI ligand and the E3 ligase ligand, thereby optimizing ternary complex formation. In addition, nucleotides can also serve as E3 ligase ligands. Oligonucleotides represent a promising approach in PROTAC design, capable of fulfilling multiple functional roles.

High fat diet promotes asthma by inhibiting the differentiation of regulatory T cells via E3 ubiquitin ligase ITCH.

This study aimed to elucidate the role of neuronaI precursor cell-expressed developmentally down-regulated 4-like (NEDD4L), a developmentally downregulated E3 ubiquitin ligase, in rheumatoid arthritis (RA). Serum NEDD4L levels in RA patients (during both stable and active disease stages) and healthy controls were measured by enzyme-linked immunosorbent assay (ELISA). Immunohistochemistry (IHC) was used to analyze NEDD4L expression in synovial tissues from RA patients compared to traumatic control subjects. In animal experiments, the proteasome inhibitor MG-132 was administered to inhibit NEDD4L degradation, and its effects on joint inflammation and bone erosion were evaluated in a collagen-induced arthritis (CIA) rat model. At the cellular level, NEDD4L overexpression and knockdown models were constructed in rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs). The effects of NEDD4L on RA-FLS proliferation, migration, and invasion were assessed using CCK-8, wound healing and Transwell assays, respectively. Transcriptome analysis of the NEDD4L-knockdown model provided further insights into the associated diseases and pathways. Finally, the impact of NEDD4L on key proteins of the Wnt/β-catenin signaling pathway (DVL2, GSK3β, p-GSK3β, β-catenin) was examined via Western blotting and immunofluorescence, systematically investigating the mechanism of NEDD4L in RA pathogenesis both in vivo and in vitro. NEDD4L expression was downregulated in the serum and synovial tissues of RA patients. Functional assays demonstrated that NEDD4L knockdown enhanced the proliferative, migratory, and invasive capacities of RA-FLSs and promoted the secretion of the pro-inflammatory cytokines IL-6 and TNF-α, whereas NEDD4L overexpression exerted opposite effects. In CIA rats, MG-132 intervention alleviated joint inflammation and bone destruction, concomitant with restored synovial NEDD4L expression. Mechanistic studies further revealed that NEDD4L influences the biological behavior of RA-FLSs by regulating key components of the Wnt/β-catenin signaling pathway. NEDD4L modulates the migration, invasion, and pro-inflammatory cytokine secretion of RA-FLSs via the Wnt/β-catenin signaling pathway, suggesting its potential as a therapeutic target for RA. Key Points • NEDD4L knockdown activates Wnt/β-catenin pathway (DVL2, GSK3β, β-catenin). • Promotes IL-6/TNF-α secretion and cell invasiveness. • NEDD4L overexpression shows opposite effects. • Potential therapeutic target for RA.

Structural optimization of AR and AR-V7 degraders incorporating silicon-based hydrophobic tags for treatment of castration-resistant prostate cancer.

FOSL2 drives acute myeloid leukemogenesis through suppression of ERAD-induced proteostatic collapse.

FBXO32 activates the PI3K/AKT pathway by inhibiting PTEN through ubiquitination of TAL1 in hepatocellular carcinoma.

Role of CIRP in glioma Progression: Inhibition of ferroptosis via UBR5-Mediated ACSL4 degradation.

ANKFY1 suppresses PDCoV replication by degrading viral nsp8 protein via p62-dependent selective autophagy.

Molecular insights for the tumor suppressor role of SPOP in prostate cancer.