Proteosome

After blue-light exposure, ubiquitination of PHOTOTROPIN1 lysine 526 enhances phototropic responses. Arabidopsis blue-light photoreceptor, PHOTOTROPIN1 (PHOT1) mediates a series of blue-light responses that function to optimize photosynthesis efficiency. Blue-light sensing through the N-terminal sensory domain activates the C-terminal kinase activity of PHOT1, resulting in autophosphorylation. In addition to phosphorylation, PHOT1 lysine residue 526 (Lys526), after blue-light exposure, was found to carry a double glycine attachment, indicative of a possible ubiquitination modification...

Mutations in genes that affect mitochondrial function cause primary mitochondrial diseases. Mitochondrial diseases are highly heterogeneous and even patients with the same mitochondrial disease can exhibit broad phenotypic heterogeneity, which is poorly understood. Mutations in subunits of mitochondrial respiratory complex I cause complex I deficiency, which can result in severe neurological symptoms and death in infancy. However, some complex I deficiency patients present with much milder symptoms. The most common nuclear gene mutated in complex I deficiency is the highly conserved core subunit NDUFS1...

We hypothesized that subjects with heterozygous loss-of-function (LoF) ACE mutations are at risk for Alzheimer's disease because amyloid Aβ42, a primary component of the protein aggregates that accumulate in the brains of AD patients, is cleaved by ACE (angiotensin I-converting enzyme). Thus, decreased ACE activity in the brain, either due to genetic mutation or the effects of ACE inhibitors, could be a risk factor for AD. To explore this hypothesis in the current study, existing SNP databases were analyzed for LoF ACE mutations using four predicting tools, including PolyPhen-2, and compared with the topology of known ACE mutations already associated with AD...

BACKGROUND: As an actin cytoskeleton interactor, PDZ and LIM domain protein 7 (PDLIM7) was supposed to play an essential role modulating cytoskeleton. Focal adhesions (FAs), which located at the cytomembrane terminus of actin cytoskeleton, function as a force sensor and can transform the mechanical signal to biochemical signal. Focal adhesion kinase (FAK) localizes to and regulates signal transduction in FAs, which play an essential role in cell polarity, migration and invasion. However, whether PDLIM7 is involved in FAs-associated signal transduction and its role in tumor invasion and metastasis remains largely unknown...

The standard treatment for canine lymphoma is the CHOP chemotherapy regimen. Proteasome inhibitors have been employed with CHOP for the treatment of human haematological malignancies but remain to be fully explored in canine lymphoma. We identified an association between poor response to CHOP chemotherapy and high mRNA expression levels of proteasomal subunits in a cohort of 15 canine lymphoma patients, and sought to determine the effect of proteasome inhibitors on the viability of a canine B-cell lymphoma cell line (CLBL-1)...

Nonalcoholic liver disease (NAFLD) encompasses a disease continuum from simple steatosis, to non-alcoholic steatohepatitis (NASH). However, there are currently no approved pharmacotherapies for NAFLD although several drugs are in advanced stages of clinical development. Because of the complex pathophysiology and heterogeneity of NALFD, identification of potential therapeutic targets is clinically important. Here, we demonstrated that TRIM56 protein abundance is markedly downregulated in the livers of individuals with NAFLD and mice fed a high-fat diet...

Flaviviruses, including Zika virus (ZIKV) and Dengue virus (DENV), rely on their non-structural protein 5 (NS5) for both replication of viral genome and suppression of host IFN signaling. DENV and ZIKV NS5s were shown to facilitate proteosome-mediated protein degradation of human STAT2 (hSTAT2). However, how flavivirus NS5s have evolved for species-specific IFN-suppression remains unclear. Here we report structure-function characterization of the DENV serotype 2 (DENV2) NS5-hSTAT2 complex. The MTase and RdRP domains of DENV2 NS5 form an extended conformation to interact with the coiled-coil and N-terminal domains of hSTAT2, thereby promoting hSTAT2 degradation in cells...

Due to evolving treatment standards for newly diagnosed multiple myeloma, many patients will be triple-class exposed after initial relapses and have poor survival. Novel therapies and combinations are therefore required to improve outcomes. B cell maturation antigen (BCMA)-targeted biologics have emerged as an important new area of therapeutics for relapsed multiple myeloma. The two-part ALGONQUIN trial evaluated various doses and schedules of the anti-BCMA antibody-drug conjugate belantamab mafodotin plus pomalidomide and dexamethasone for patients who are lenalidomide refractory and proteosome inhibitor exposed...

Lysosomal degradation of autophagy receptors is a common proxy for selective autophagy. However, we find that two established mitophagy receptors, BNIP3 and BNIP3L/NIX, are constitutively delivered to lysosomes in an autophagy-independent manner. This alternative lysosomal delivery of BNIP3 accounts for nearly all its lysosome-mediated degradation, even upon mitophagy induction. To identify how BNIP3, a tail-anchored protein in the outer mitochondrial membrane, is delivered to lysosomes, we performed a genome-wide CRISPR screen for factors influencing BNIP3 flux...

Sine oculis homeobox homolog 1 (Six1) is a developmentally important transcription factor that regulates cellular proliferation, apoptosis, and dissemination during embryogenesis. Six1 overexpression as reported in multiple cancers modulates expression of a repertoire of its target genes causing an increase in proliferation, metastasis and survival of cancer cells. Six1 exists as a cell cycle regulated nuclear phosphoprotein and its cellular turnover is regulated by APC/C (Anaphase promoting complex / Cyclosome) complex mediated proteolysis...

Despite the promising antitumor activity of SHP2 inhibitors in RAS-dependent tumours, overall responses have been limited by their narrow therapeutic window. Like with all MAPK pathway inhibitors, this is likely the result of compensatory pathway activation mechanisms. However, the underlying mechanisms of resistance to SHP2 inhibition remain unknown. The E3 ligase SMURF2 limits TGFβ activity by ubiquitinating and targeting the TGFβ receptor for proteosome degradation. Using a functional RNAi screen targeting all known phosphatases, we identify that the tyrosine phosphatase SHP2 is a critical regulator of TGFβ activity...

Strategies for patient stratification and early intervention are required to improve clinical benefits for patients with prostate cancer. Here, we found that active DHEA utilization in the prostate gland correlated with tumor aggressiveness at early disease stages, and 3βHSD1 inhibitors were promising for early intervention. [3H]-labeled DHEA consumption was traced in fresh prostatic biopsies ex vivo. Active DHEA utilization was more frequently found in patients with metastatic disease or therapy-resistant disease...

Reactive Oxygen Species (ROS) play an essential role in the pathogenesis of osteoporosis mainly characterized by excessive osteoclasts (OCs) activity. OCs are rich in mitochondria for energy support, which is a major source of total ROS. Tussilagone (TSG), a natural Sesquiterpenes from the flower of Tussilago farfara, has plentiful beneficial pharmacological characteristics with anti-inflammatory and anti-oxidative activity, but its effects and mechanism in osteopathology are still unclear. In our study, we investigated the regulation of ROS generated from the mitochondria in OCs...

BACKGROUND/OBJECTIVES: Inonotus obliquus has been used as antidiabetic herb around the world, especially in the Russian and Scandinavian countries. Diabetes is widely believed to be a key factor in Alzheimer's disease (AD), which is widely considered to be type III diabetes. To investigate whether I. obliquus can also ameliorate AD, it would be interesting to identify new clues for AD treatment. We tested the anti-AD effects of raw Inonotus obliquus polysaccharide (IOP) in a mouse model of AD (3×Tg-AD transgenic mice)...

Regulation of tumoral PD-L1 expression is critical to advancing our understanding of tumor immune evasion and the improvement of existing antitumor immunotherapies. Herein, we describe a CRISPR-based screening platform and identified ATXN3 as a positive regulator for PD-L1 transcription. TCGA database analysis revealed a positive correlation between ATXN3 and CD274 in more than 80% of human cancers. ATXN3-induced Pd-l1 transcription was promoted by tumor microenvironmental factors, including the inflammatory cytokine IFN-γ and hypoxia, through protection of their downstream transcription factors IRF1, STAT3, and HIF-2α...

BACKGROUND: TGFβ induces several cell phenotypes including senescence, a stable cell cycle arrest accompanied by a secretory program, and epithelial-mesenchymal transition (EMT) in normal epithelial cells. During carcinogenesis cells lose the ability to undergo senescence in response to TGFβ but they maintain an EMT, which can contribute to tumor progression. Our aim was to identify mechanisms promoting TGFβ-induced senescence escape. METHODS: In vitro experiments were performed with primary human mammary epithelial cells (HMEC) immortalized by hTert...

BACKGROUND: Alzheimer's disease (AD) is characterized by neuroinflammation linked to amyloid β (Aβ) aggregation and phosphorylated tau (τ) protein in neurofibrillary tangles (NFTs). Key elements in Aβ production and NFT assembly, like γ-secretase and p38 mitogen-activated protein kinase (p38MAPK), contribute to neuroinflammation. In addition, impaired proteosomal and autophagic pathways increase Aβ and τ aggregation, leading to neuronal damage...

The current work demonstrates the synthesis and characterization of piperic acid conjugates with homochiral/heterochiral dipeptides containing phenylalanine as anti-skin cancer agents. The conjugates PA-D Phe-L Phe-OH, FC-1; PA-L Phe-D Phe-OH, FC-2; PA-D Phe-D Phe-OH, FC-3; and PA-D Phe-D Phe-OH, FC-4 were synthesized, characterized and assessed for cytotoxicity against melanoma cell lines of human and murine origin. Among all, PA-D Phe-D Phe (FC-3) conjugate was identified as a potential cytotoxic lead against melanoma cells by delineating the anti-proliferative and anti-migratory potential together with its anti-inflammatory potential against pro-inflammatory interleukins (IL-1β, IL-6, and IL-8)...

Chimeric antigen receptor (CAR) T cell therapy has been successful for hematological malignancies. Still, a lack of efficacy and potential toxicities have slowed its application for other indications. Furthermore, CAR T cells undergo dynamic expansion and contraction in vivo that cannot be predicted or controlled. Therefore, the safety and utility of such therapies could be enhanced by engineered mechanisms that engender reversible control and quantitative monitoring. Here, we use a genetic tag based on the enzyme E...

Many cancers harbor homologous recombination defects (HRDs). A HRD is a therapeutic target that is being successfully utilized in treatment of breast/ovarian cancer via synthetic lethality. However, canonical HRD caused by BRCAness mutations do not prevail in liver cancer. Here we report a subtype of HRD caused by the perturbation of a proteasome variant (CDW19S) in hepatitis B virus-bearing (HBV-bearing) cells. This amalgamate protein complex contained the 19S proteasome decorated with CRL4WDR70 ubiquitin ligase, and assembled at broken chromatin in a PSMD4Rpn10- and ATM-MDC1-RNF8-dependent manner...