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Correction: PIGL promotes the docetaxel resistance of prostate cancer and is regulated by E3 ubiquitin ligase HUWE1.

[This corrects the article DOI: 10.3389/fimmu.2026.1740132.].

Loss of the E3 ubiquitin ligase MARCHF6 alters hepatic lipid metabolism and drives spontaneous hepatosteatosis.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, steatohepatitis (MASH), feature excessive hepatic fat accumulation, yet the relative contributions of dietary vs. endogenous fats and their interactions has remained enigmatic. Here, we identify the endoplasmic reticulum-associated E3 ubiquitin ligase MARCHF6 as a pivotal regulator of hepatic lipid metabolism. Global or hepatocyte-specific deletion of Marchf6 induced spontaneous accumulation of triglycerides and cholesteryl esters under chow-fed conditions, revealing a cell-autonomous hepatic defect inde

The autoimmune regulator (AIRE) is a target of the E3-Ubiquitin ligase Seven-in-absentia homolog 1 (SIAH1).

The autoimmune regulator (AIRE) is expressed in medullary thymic epithelial cells (mTECs) and is crucial for generating an immunocompetent T cell repertoire during central tolerance. Loss of AIRE function causes autoimmune polyglandular syndrome type 1 (APS-1), also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). Intracellular proteins are regulated by ubiquitination pathways. E3 ubiquitin ligases are specific proteins that confer selectivity to polyubiquitination, tagging proteins for proteasomal degradation while also performing other functions. In mTECs, pe…

The E3 Ligase RNF115 Aggravates Pathological Cardiac Hypertrophy via Ubiquitin-Mediated Degradation of SPTBN1.

Pathological cardiac hypertrophy represents an adaptive alteration in cardiac structure and function and serves as a critical process in heart failure. Ubiquitination, a classical post-translational modification that regulates protein function and degradation, plays a crucial role in cardiac hypertrophy. In this study, the E3 ubiquitin ligase ring finger protein 115 (RNF115) is identified as a key pro-hypertrophic factor. RNF115 expression is significantly elevated in heart tissues from patients with heart failure, in mice subjected to transverse aortic constriction (TAC) surgery, and in cardi

The ZBTB16/CUL3/ROC1 ubiquitin ligase drives the degradation of pathogenic pendrin (SLC26A4) protein variants.

BACKGROUND: Pathogenic sequence alterations in the SLC26A4 gene, which encodes the solute carrier SLC26A4/pendrin, lead to Pendred syndrome and non-syndromic autosomal recessive deafness type B4 (DFNB4), two of the most common forms of hearing loss worldwide. Many pathogenic SLC26A4 protein variants exhibit reduced cellular levels due to ubiquitin-proteasome system (UPS)-mediated degradation, and UPS inhibition rescues their plasma membrane expression and ion transport function. However, the underlying molecular mechanisms remain unclear and may involve interactions with novel molecular partne

Targeting D-alanine ligase from methicillin-resistant Staphylococcus aureus using natural compounds.

Methicillin-resistant Staphylococcus aureus (MRSA) infections pose a critical threat in healthcare and community settings. Meanwhile, the effectiveness of treatment is limited by vancomycin, which remains the only frontline drug against MRSA. The emergence of new strains of MRSA, along with the development of vancomycin-resistant S. aureus (VRSA), emphasises the need for alternative therapies. This study explores the use of natural compounds as a sustainable alternative to treat MRSA. The inhibition potential of natural compounds against D-alanine-d-alanine ligase, a key enzyme in the peptidog

[Latest Research Progress of E3 Ubiquitin Ligase in the Diagnosis and Treatment of Acute Myeloid Leukemia --Review].

E3 ubiquitin ligase is a key enzyme that determines substrate specificity during ubiquitination and plays an important role in regulating the degradation of tumor suppressor or oncogenic proteins. E3 ubiquitin ligase is involved in regulating leukemia cell differentiation, cell cycle and immune response, and it is closely related to the occurrence and development of acute myeloid leukemia (AML). Targeting highly specific E3 ubiquitin ligase can be used as an effective treatment for AML. This article reviewed the latest progress of E3 ubiquitin ligase in the diagnosis and treatment of AML, aimi

Ebastine-mediated destabilization of E3 ligase MKRN1 protects against metabolic dysfunction-associated steatohepatitis.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic condition encompassing metabolic dysfunction-associated steatotic liver (MASL) and metabolic dysfunction-associated steatohepatitis (MASH), which can progress to fibrosis, cirrhosis, or hepatocellular carcinoma (HCC). The heterogeneous and complex nature of MASLD complicates optimal drug development. Ebastine, an antihistamine, exhibits antitumor activity in various types of cancer. However, its effects on MASH remain unexplored. In the present study, we identified ebastine as a potential treatment for MASH. Our resu

DCAF12 Ubiquitin Ligase Promotes Lung Cancer Metastasis by Modulating the TRiC/CCT Chaperonin Complex.

Metastasis is the primary challenge in lung cancer treatment. Although proteostasis supports tumor growth, the mechanism by which ubiquitin ligases reprogram chaperone networks to drive metastasis is poorly understood. In this study, it is revealed that DDB1-CUL4-associated factor (DCAF12), a substrate receptor for CUL4-RING ubiquitin ligases, regulates metastatic progression through ubiquitin-mediated proteostatic reprogramming. DCAF12 depletion suppresses tumor cell migration and stemness in vitro and reduces pulmonary/hepatic metastasis in vivo. Mechanistically, DCAF12 catalyzes the non-deg…

Recombinant antibodies inhibit enzymatic activity of the E3 ubiquitin ligase CHIP via multiple mechanisms.

Carboxyl-terminus of Hsp70-Interacting Protein (CHIP) is an E3 ubiquitin ligase that marks misfolded substrates for degradation. Hyper-activation of CHIP has been implicated in multiple diseases, including cystic fibrosis and cancer, suggesting that it may be a potential drug target. However, there are few tools available for exploring this possibility. Moreover, the best ways of inhibiting CHIP's function are not obvious, as this complex protein is composed of a tetratricopeptide repeat (TPR) domain, a U-box domain, and a coiled-coil domain that mediates homodimerization. To probe the structu

The adaptability of the fungal tRNA ligase's ATP-binding pocket: a potential target for new antifungal drugs.

The transfer RNA (tRNA) ligase (TRL1) is a highly conserved multidomain protein that is the archetype of the recently characterized Rnl6 clade. This clade distinguishes itself through a distinct C-terminal domain that sets it apart from other RNA ligase families. TRL1 is an essential component of pre-tRNA splicing and the processing of the Ire1p (Inositol-requiring enzyme 1)-dependent noncanonical splicing of the messenger RNA (mRNA) coding for HAC-1 (Homologous to Activating Transcription Factor / cAMP Response Element-Binding Protein 1 (ATF/CREB1), a transcription factor critical for the unf

Structure-based drug repurposing and experimental validation of inhibitors targeting LigaseD from Mycobacterium tuberculosis.

Mycobacterium tuberculosis (Mtb) remains a major global health threat due to its survival under host-induced stress and the rise of drug-resistant strains. One critical factor contributing to this resilience is its ability to efficiently repair DNA damage. To survive double-stranded DNA breaks, Mtb utilizes two pathways: homologous recombination (HR) and non-homologous end joining (NHEJ). During dormancy, when HR is less active, Mtb predominantly relies on NHEJ, a pathway involving Ku and LigaseD. LigaseD catalyses DNA ligation through its ligase domain (LigDom), which comprises two subdomains

The E3 ubiquitin ligase adaptor KLHL8 targets ZAR1 to regulate maternal mRNA degradation in oocytes.

Maternal protein homeostasis and timely degradation of maternal mRNAs are essential for meiotic cell-cycle progression and subsequent embryonic development, but the mechanisms of maternal protein degradation are poorly understood. Here, we show that KLHL8, a substrate adaptor of Cullin-RING E3 ubiquitin ligases, is highly expressed in mouse oocytes and co-localizes with mitochondria. Oocyte-specific deletion of Klhl8 causes oocyte maturation defects and female infertility. ZAR1, an RNA binding protein that is required for mitochondria-associated ribonucleoprotein domain (MARDO) dissolution, is…

Recessive variants in WSB2 encoding a substrate receptor of E3 ubiquitin ligase underlie a neurodevelopmental syndrome.

WD40 and SOCS box protein-2 (WSB2), a member of the large family of suppressor of cytokine signaling (SOCS)-box proteins, has recently been identified as a substrate receptor of cullin 5 E3 ligase that plays an important role in proteomic regulation through substrate ubiquitination and proteasomal degradation. Here we report five patients from four unrelated families presenting with neurodevelopmental delay, dysmorphic features, brain structural abnormalities with or without growth restriction, hypotonia, and microcephaly, all of whom are homozygous for extremely rare and predicted loss-of-fun

E3 Ligase Rbx1 Orchestrates Thymus Development and Fate Determination of αβ-γδ T Cells.

T lymphocytes consist of αβ and γδ T cells, which mature and differentiate from the same progenitor cells in the thymus. Cullin-RING ligases (CRLs), the largest family of ubiquitin ligases, require neddylation on the scaffold protein Cullins for their ligase activity. The role of neddylation-CRL system in thymus development and fate determination of αβ/γδ T cells remains elusive. Here, we generated conditional knockout mouse models with thymus individual deletion of Ube2m or Ube2f, 2 neddylation E2-conjugating enzymes, and Rbx1 or Sag, 2 dual neddylation and ubiquitylation E3 ligases. We found…

Nuclear p62 condensates stabilize the promyelocytic leukemia nuclear bodies by sequestering their ubiquitin ligase RNF4.

Liquid-liquid phase separation has emerged as a crucial mechanism driving the formation of membraneless biomolecular condensates, which play important roles in numerous cellular processes. These condensates, found both in the nucleus and cytoplasm, are formed through multivalent, low-affinity interactions between various molecules. P62-containing condensates serve, among other functions, as proteolytic hubs for the ubiquitin-proteasome system. In this study, we investigated the dynamic interplay between nuclear p62 condensates and promyelocytic nuclear bodies (PML-NBs). We show that p62 conden

Mezigdomide-A Novel Cereblon E3 Ligase Moduler под следствием в Replapsed/ Refractory Multieloma.

Mezigomide — пероральный модулятор лигаса Е3 (CELMOD), который находится под клиническим исследованием у пациентов с множественным миэломой (MM) responsed/refractory (RR). Как и другие соединения CELMOD, мезигдомид действует, изменяя конформацию церебрально-церебрального узла Cullin 4A кольца Ligase-Cereblon (CRL4CRBN) E3 Ubisquitin Ligase, тем самым привлекая новые белковые субстраты для селективной протеасомальной деградации. К ним относятся: two Критические лимфоидные коэффициенты транскрипции, протеины цинкового пальца семейства Икарос 1 и 3 (IKZF1 и IKZF3), также известные как Ikaros и Ai

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… One such approach has been to target specific E3 ligases and substrate proteins. … As noted, multiple E3 ligases are involved in protein degradation by the UPS, including the cullin-RING ligases (CRLs), which incorporate a variety of substrate recruiters or receptors in order to degrade a range of substrate proteins ( Figure 1 ). …

The E3 ligase TRIM22 restricts SARS-CoV-2 replication by promoting proteasomal degradation of NSP8.

Replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome is mediated by a complex of non-structural proteins (NSPs), of which NSP7 and NSP8 serve as subunits and play a key role in promoting the activity of RNA-dependent RNA polymerase (RdRp) of NSP12. However, the stability of subunits of the RdRp complex has rarely been reported. Here, we found that NSP8 was degraded by the proteasome in host cells, and identified tripartite motif containing 22 (TRIM22) as its E3 ligase. The interferon (IFN) signaling pathway was activated upon viral invasion into host cells, and TR

Inhibition of the E3 ligase UBR5 stabilizes TERT and protects vascular organoids from oxidative stress.

BACKGROUND: Excessive oxidative stress is known to cause endothelial dysfunction and drive cardiovascular diseases (CVD). While telomerase reverse transcriptase (TERT) shows protective effects against oxidative stress in rodents and is associated to human flow-mediated dilation in CVD, its regulatory mechanisms in human vascular systems under pathological oxidative stress require further investigation. METHODS: Human induced pluripotent stem cells (hiPSCs) were used to create vascular organoids (VOs). These VOs and human umbilical vein endothelial cells (HUVECs) were subjected to oxidative st