Plasma membrane repair is an essential process for maintenance of homeostasis at the cellular and tissue levels, whereas compromised repair capacity contributes to degenerative human diseases. Our recent studies show that MG53 is essential for muscle membrane repair, and defects in MG53 function are linked to muscular dystrophy and cardiac dysfunction. Here we report that polymerase I and transcript release factor (PTRF), a gene known to regulate caveolae membrane structure, is an indispensable component of the membrane repair machinery. PTRF acts as a docking protein for MG53 during membrane repair potentially by binding exposed membrane cholesterol at the injury site. Cells lacking expression of endogenous PTRF show defective trafficking of MG53 to membrane injury sites. A mutation in PTRF associated with human disease results in aberrant nuclear localization of PTRF and disrupts MG53 function in membrane resealing. Although RNAi silencing of PTRF leads to defective muscle membrane repair, overexpression of PTRF can rescue membrane repair defects in dystrophic muscle. Our data suggest that membrane-delimited interaction between MG53 and PTRF contributes to initiation of cell membrane repair, which can be an attractive target for treatment or prevention of tissue injury in human diseases.Repair of acute damage to the plasma membrane is an important aspect of cellular physiology, and disruption of this process can contribute to pathophysiology in a number of human diseases including muscular dystrophy and heart failure (1-5). Several previous studies established the framework of the cell membrane repair response that involves translocation of intracellular vesicles to the injury site to form a membrane repair patch (6, 7). We recently discovered that MG53 protein is an essential component of the membrane repair machinery (8 -11). We showed that MG53 ablation results in defective sarcolemmal membrane repair with progressive myopathy (11) and increased vulnerability of the heart to exercise stress and ischemia reperfusion-induced injury (9, 10). Because MG53 can discriminate between intact and injured membrane (10), a membrane-delimited signal would likely be involved in tethering MG53 to the injured site. Identification of such an anchoring molecule is essential for our understanding of the basic biology of membrane resealing, as well as for designing therapeutic means to improve membrane repair defects in human diseases.Caveolae are specialized plasma membrane invaginations that play important roles in many cellular processes. Caveolins are major coating proteins of caveolae, and mutations in caveolins have been identified in various human diseases (12-15). Our previous study showed that MG53 can interact with caveolin-3, and altered interaction between MG53 and caveolin-3 is linked to membrane repair defects in muscular dystrophy (8). In addition to caveolins, the polymerase I and transcript release factor (PTRF), 3 also known as cavin-1 (16), is enriched in caveolae and contributes to the stable formation of c...

Mitochondria-targeting peptides have garnered immense interest as potential chemotherapeutics in recent years. However, there is a clear need to develop strategies to overcome the critical limitations of peptides, such as poor solubility and the lack of target specificity, which impede their clinical applications. To this end, we report magnetic core–shell nanoparticle (MCNP)-mediated delivery of a mitochondria-targeting pro-apoptotic amphipathic tail-anchoring peptide (ATAP) to malignant brain and metastatic breast cancer cells. Conjugation of ATAP to the MCNPs significantly enhanced the chemotherapeutic efficacy of ATAP, while the presence of targeting ligands afforded selective delivery to cancer cells. Induction of MCNP-mediated hyperthermia further potentiated the efficacy of ATAP. In summary, a combination of MCNP-mediated ATAP delivery and subsequent hyperthermia resulted in an enhanced effect on mitochondrial dysfunction, thus resulting in increased cancer cell apoptosis.

Toll-like receptor (TLR) pathways signal through microbial components stimulation to induce innate immune responses. Herein, we demonstrate that BCL10, a critical molecule that signals between the T cell receptor and IB kinase complexes, is involved in the innate immune system and is required for appropriate TLR4 pathway and nuclear factor-B (NF-B) activation. In response to lipopolysaccharide (LPS) stimulation, BCL10 was recruited to TLR4 signaling complexes and associated with Pellino2, an essential component downstream of BCL10 in the TLR4 pathway. In a BCL10-deficient macrophage cell line, LPS-induced NF-B activation was consistently defective, whereas activator protein-1 and Elk-1 signaling was intact. In addition, we found that BCL10 was targeted by SOCS3 for negative regulation in LPS signaling. The recruitment of BCL10 to TLR4 signaling complexes was attenuated by induced expression of SOCS3 in a feedback loop. Furthermore, ectopic SOCS3 expression blocked the interaction between BCL10 and Pellino2 together with BCL10-generated NF-B activation and inducible nitric-oxide synthase expression. Together, these data define an important role of BCL10 in the innate immune system.

The pH-responsive PTX-loaded micelles are promising candidates in developing stimuli triggered drug delivery systems in acidic tumor microenvironments with improved inhibitory effects on tumor metastasis.

Thyroid hormone receptor β1 (TRβ1) is a ligand‑dependent transcription factor that belongs to the superfamily of nuclear receptors. TRβ1 has been found to act as a tumor suppressor in many solid tumors including breast cancer and hepatocellular carcinoma, but its role in the progression of human colorectal cancer (CRC) remains unclear. In this study, microarray data analysis revealed that TRβ1 mRNA was downregulated in CRC tumors compared with that in the normal counterparts in both The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. Using a CRC tissue microarray (TMA), we confirmed that the expression of TRβ1 was decreased in human CRC tumor tissues in contrast to normal colorectal mucosal tissues. Notably, the TRβ1 expression was strongly correlated with tumor size (p=0.045). Furthermore, we found that CRC cell proliferation and migration were significantly inhibited by TRβ1 overexpression in vitro. Mechanistic studies indicated that activated phosphorylated Akt was clearly suppressed by TRβ1 in the CRC tissues and cells. In conclusion, this study provides evidence that TRβ1 plays a critical role in the progression of CRC via the PI3K/Akt pathway, and the TRβ1 gene may represent a novel target for CRC therapeutics.