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Protein breakdown in muscle wasting: role of autophagy-lysosome and ubiquitin-proteasome.

Skeletal muscle adapts its mass as consequence of physical activity, metabolism and hormones. Catabolic conditions or inactivity induce signaling pathways that regulate the process of muscle loss. Muscle atrophy in adult tissue occurs when protein degradation rates exceed protein synthesis. Two major protein degradation pathways, the ubiquitin-proteasome and the autophagy-lysosome systems, are activated during muscle atrophy and variably contribute to the loss of muscle mass. These degradation systems are controlled by a transcription dependent program that modulates the expression of rate-lim

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… Importantly, the muscle-specific atrophy-related ubiquitin ligases atrogin1/MAFbx and MuRF1 similarly to other E3s, undergo auto-ubiquitination ( Bodine et al., 2001 ). … The ubiquitin-proteasome In the ubiquitin-proteasome system, proteins are targeted for degradation by the 26S proteasome through covalent attachment of a chain of ubiquitin molecules. …

MG132-mediated inhibition of the ubiquitin-proteasome pathway ameliorates cancer cachexia.

PURPOSE: To evaluate the effect of proteasome inhibitor MG132 in cancer cachexia and to delineate the molecular mechanism underlying. METHODS: We established an experimental cancer cachexia model by subcutaneously implanting colon 26 cells into the armpits of BALB/c mice. Following administration of MG132 at various time points, body weight, food intake, gastrocnemius muscle weight, spontaneous activity and survival of tumor-bearing mice were examined along with tumor growth. Moreover, cachectic markers including glucose, triglyceride, albumin and total proteins as well as levels of the proin

Structure of a RING E3 ligase and ubiquitin-loaded E2 primed for catalysis.

Ubiquitin modification is mediated by a large family of specificity determining ubiquitin E3 ligases. To facilitate ubiquitin transfer, RING E3 ligases bind both substrate and a ubiquitin E2 conjugating enzyme linked to ubiquitin via a thioester bond, but the mechanism of transfer has remained elusive. Here we report the crystal structure of the dimeric RING domain of rat RNF4 in complex with E2 (UbcH5A) linked by an isopeptide bond to ubiquitin. While the E2 contacts a single protomer of the RING, ubiquitin is folded back onto the E2 by contacts from both RING protomers. The carboxy-terminal

Yeast Rsp5 ubiquitin ligase affects the actin cytoskeleton in vivo and in vitro.

Yeast Rsp5 ubiquitin ligase is involved in several cellular processes, including endocytosis. Actin patches are sites of endocytosis, a proc … rease was prevented in a strain devoid of Las17-binding protein Sla1 which is also a target of Rsp5 ubiquitination. Thus, Rsp5 together with Lsb1, Lsb2 and Sla1 regulate the level of Las17, an important activator of actin polymerization.

Ubiquitin carboxyl-terminal hydrolase l3 promotes insulin signaling and adipogenesis.

Insulin is a potent adipogenic hormone that triggers the induction of a series of transcription factors and specific proteins governing the differentiation of preadipocytes into mature adipocytes. Here we report that ubiquitin carboxyl-terminal hydrolase (UCH)-L3, a deubiquitinating enzyme, promotes insulin signaling and adipogenesis. Uchl3(-/-) mice had less visceral white adipose tissue compared with wild-type mice. In vitro adipogenesis experiments revealed that mouse embryonic fibroblasts (MEFs) and preadipocytes from Uchl3(-/-) mice had impaired ability to differentiate into mature adipoc

Diversification of a Salmonella virulence protein function by ubiquitin-dependent differential localization.

Many bacterial pathogens and symbionts utilize type III secretion systems to deliver bacterial effector proteins into host cells. These effector proteins have the capacity to modulate a large variety of cellular functions in a highly regulated manner. Here, we report that the phosphoinositide phosphatase SopB, a Salmonella Typhimurium type III secreted effector protein, diversifies its function by localizing to different cellular compartments in a ubiquitin-dependent manner. We show that SopB utilizes the same enzymatic activity to modulate actin-mediated bacterial internalization and Akt acti

Role of UCH-L1/ubiquitin in acute testicular ischemia-reperfusion injury.

The most significant complication of testicular torsion is loss of the testis, which may lead to impaired fertility. Molecular mechanisms ho … in carboxyl-terminal hydrolase-L1 (UCH-L1) at both mRNA and protein levels. To test further whether ubiquitination was involved in IR stress, both mono- and poly-ubiquitin levels in IR stress condition were examined, which showed that both mono- and poly-ubiquitin expression significantly impaired. These results provide evidences of UCH-L1/ubiquitination signali …

Role of ubiquitin-like protein FAT10 in epithelial apoptosis in renal disease.

Dysregulated apoptosis of renal tubular epithelial cells (RTEC) is an important component of the pathogenesis of several renal diseases, including HIV-associated nephropathy (HIVAN), the most common cause of chronic kidney failure in HIV-infected patients. In HIVAN, RTEC become infected by HIV-1 in a focal distribution, and HIV-1 infection has been shown to induce apoptosis in vitro. In microarray studies that used a novel renal tubular epithelial cell line from a patient with HIVAN, it was found that the ubiquitin-like protein FAT10 is one of the most upregulated genes in HIV-infected cells.

Essential role of ubiquitin-proteasome system in normal regulation of insulin secretion.

Insulin secretion from pancreatic beta-cells occurs by sequential cellular processes, including glucose metabolism, electrical activity, Ca2 … of the impaired insulin secretion. We found that the pore-forming alpha-subunit of VDCCs undergoes ubiquitination, which does not decrease but slightly increases expression of the alpha-subunit protein at the plasma membrane. However, electrophysiological analysis revealed that treatment with proteasome inhibitors results in a severe reduction in VDCC activity …

Hippocampal sclerosis and ubiquitin-positive inclusions in dementia lacking distinctive histopathology.

The aim of this study was to determine the frequency of ubiquitin-positive inclusions (UPI) in dementia lacking distinctive histology (DLDH), and their relationship to other pathologic features, such as hippocampal sclerosis (HpScl), as well as genetic factors. Routine and immunohistochemical studies were carried out in a consecutive series of 29 cases of DLDH. 83% of the cases had UPI, while HpScl was demonstrated in 76%. There was no significant correlation among pathologic features or between pathologic features and genetic factors. The high prevalence of UPI demonstrated in this study impl

A ubiquitin-proteasome pathway represses the Drosophila immune deficiency signaling cascade.

BACKGROUND: The inducible production of antimicrobial peptides is a major immune response in Drosophila. The genes encoding these peptides are activated by NF-kappaB transcription factors that are controlled by two independent signaling cascades: the Toll pathway that regulates the NF-kappaB homologs, Dorsal and DIF; and the IMD pathway that regulates the compound NF-kappaB-like protein, Relish. Although numerous components of each pathway that are required to induce antimicrobial gene expression have been identified, less is known about the mechanisms that either repress antimicrobial genes i

Immunocytochemical co-localization of the proteasome in ubiquitinated structures in neurodegenerative diseases and the elderly.

To determine at the tissue level whether the proteasome (Ps), a unique nonlysosomal protease, is involved in the metabolism of ubiquitinated proteins, we examined for the first time the immunocytochemical localizations of both Ps and ubiquitin (Ub) in sections of various abnormal structures that are known to be ubiquitinated in various neurodegenerative diseases and in the elderly. Concomitant increases of Ps and Ub were observed at the sites of most dystrophic neurites in Alzheimer disease (AD) and parkinsonism-dementia complex on Guam (PDC) and in Lewy bodies in Parkinson's disease and diffu

Hippocampal and neocortical ubiquitin-immunoreactive inclusions in amyotrophic lateral sclerosis with dementia.

Amyotrophic lateral sclerosis (ALS) patients with dementia were found to have ubiquitin-immunoreactive (IR) inclusions in the dentate granule cells of the hippocampus. These inclusions were also present in some patients with minor cognitive changes but otherwise typical ALS. Ubiquitin-IR inclusions were also found in neurons of superficial layers of the frontal and temporal cortex and in the entorhinal cortex in patients with ALS and dementia. These ubiquitin-IR inclusions were non-argyrophilic, and were not labelled by antibodies which identify Alzheimer's neurofibrillary tangles and Pick bod

Interferon induces a 15-kilodalton protein exhibiting marked homology to ubiquitin.

Immunochemical methods were used to examine the effect of viral infection on the dynamics of intracellular ubiquitin pools. Infection of either the human lung carcinoma line A-549 or the mouse fibroblast line L929 with encephalomyocarditis virus had little effect on either the distribution or fractional level of intracellular ubiquitin conjugates. In contrast, viral infection resulted in a significant decline in the steady state content of the mono-ubiquitin conjugate to histone 2A (uH2A). Prior treatment with interferons protected against this decrease of uH2A. Furthermore, interferons induce

Acetylation-ubiquitination crosstalk in NLRP3-gasdermin pyroptosis: a substrate-state framework with relevance to ulcerative colitis.

Acetylation and ubiquitination regulate inflammatory cell death, but evidence that they act together in ulcerative colitis (UC) remains limited. This review examines their interactions in nucleotide-binding oligomerisation domain-, leucine-rich repeat- and pyrin domain-containing protein 3 (NLRP3) and gasdermin D (GSDMD), drawing on a targeted PubMed search for literature published through 10 August 2026. We distinguish coupling tested within one study from separate mechanisms affecting the same substrate, and report human, intestinal and non-intestinal evidence separately. Studies of phosphog…

Usp3 negatively regulates Mda5-mediated antiviral response by attenuating its K63-linked ubiquitination in black carp.

Melanoma differentiation-associated gene 5 (MDA5) is a critical cytosolic RNA sensor that initiates type I interferon (IFN) signaling upon v … rectly interacts with bcMda5. Furthermore, bcUsp3 over-expression reduced both total and K63-linked ubiquitination of bcMda5, indicating that bcUsp3 attenuates the K63-linked ubiquitination of bcMda5. Collectively, our findings demonstrate that bcUsp3 functions as a negative regulator of bcMda5-mediated Ifn signaling by attenuating its K63-linked ubiquitination, …

A20 promotes OPN ubiquitination and degradation to inhibit cell growth and invasion in human hepatocellular carcinoma.

Abnormal osteopontin (OPN) expression has been implicated in hepatocellular carcinoma (HCC) progression. In this study, we assessed the prognostic value and biological functions of OPN in HCC. We also identified that A20 interacts with OPN and promotes OPN ubiquitination and protein degradation through the ubiquitin-proteasome system. The reduction in OPN levels induced by A20 attenuates OPN-associated proliferative and migratory phenotypes in HCC cells. Notably, advanced HCC tissues exhibited elevated OPN levels, while A20 expression showed variable patterns in clinical samples. In the clinic…

Construction of a ubiquitination-related gene signature to predict prognosis and treatment response in lung adenocarcinoma.

BACKGROUND & OBJECTIVE: The prognosis of lung adenocarcinoma (LUAD) remains poor, primarily due to treatment resistance and a lack of effective biomarkers. This research investigated the potential of ubiquitination-related genes (UbRG) as prognostic indicators for LUAD. METHODOLOGY: This study was conducted at Tianjin Medical University Cancer Institute and Hospital from May 2025 to October 2025. Leveraging data from TCGA, we initially employed WGCNA to identify key modules of UbRG associated with LUAD. Then, a multigene prognostic signature was developed. To investigate the mechanisms, GSEA …

BPHL promotes TNBC stemness by resolving R-loops via POLR2A lactylation inhibition and BARD1-mediated ubiquitination.

Triple-negative breast cancer (TNBC) poses a formidable clinical challenge due to its aggressive behavior and limited therapeutic avenues. H … ys.Mechanistically, BPHL engages POLR2A, curtailing its lactylation while augmenting BARD1-mediated ubiquitination to resolve R-loops and enable β-catenin nuclear translocation, thereby perpetuating Wnt signaling. Beyond intrinsic tumor programs, low R-loop states were also associated with enhanced intercellular communication (notably MIF/MK signaling) and eleva …

UBB as an early-stage potential biomarker for breast cancer via modulation of the ubiquitination pathway.

Breast cancer ranks second leading cause of cancer related mortality worldwide, emphasizing the need of early diagnosis to improve therapeutic outcomes and disease-free survival. Ubiquitin, a highly conserved protein binds to target proteins to alter their functions, stability, and signaling activity. Multiple ubiquitination forms polyubiquitin chains, which may lead to proteasomal degradation and influence major signaling pathways. In this study, we demonstrate the potential of polyubiquitin B (UBB) as a promising biomarker for early stage breast cancer. We investigated the expression of UBB …