Alzheimer's disease (AD) is an age‐related neurodegenerative disease. The most common pathological hallmarks are amyloid plaques and neurofibrillary tangles in the brain. In the brains of patients with AD, pathological tau is abnormally accumulated causing neuronal loss, synaptic dysfunction, and cognitive decline. We found a histone deacetylase 6 (HDAC6) inhibitor, CKD‐504, changed the tau interactome dramatically to degrade pathological tau not only in AD animal model (ADLPAPT) brains containing both amyloid plaques and neurofibrillary tangles but also in AD patient‐derived brain organoids. Acetylated tau recruited chaperone proteins such as Hsp40, Hsp70, and Hsp110, and this complex bound to novel tau E3 ligases including UBE2O and RNF14. This complex degraded pathological tau through proteasomal pathway. We also identified the responsible acetylation sites on tau. These dramatic tau‐interactome changes may result in tau degradation, leading to the recovery of synaptic pathology and cognitive decline in the ADLPAPT mice. 相似文献
To ensure proper transmission of genetic information, cells need to preserve and faithfully replicate their genome, and failure to do so leads to genome instability, a hallmark of both cancer and aging. Defects in genes involved in guarding genome stability cause several human progeroid syndromes, and an age‐dependent accumulation of mutations has been observed in different organisms, from yeast to mammals. However, it is unclear whether the spontaneous mutation rate changes during aging and whether specific pathways are important for genome maintenance in old cells. We developed a high‐throughput replica‐pinning approach to screen for genes important to suppress the accumulation of spontaneous mutations during yeast replicative aging. We found 13 known mutation suppression genes, and 31 genes that had no previous link to spontaneous mutagenesis, and all acted independently of age. Importantly, we identified PEX19, encoding an evolutionarily conserved peroxisome biogenesis factor, as an age‐specific mutation suppression gene. While wild‐type and pex19Δ young cells have similar spontaneous mutation rates, aged cells lacking PEX19 display an elevated mutation rate. This finding suggests that functional peroxisomes may be important to preserve genome integrity specifically in old cells. 相似文献
Plasmonics - The effects of surface plasmon (SP) coupling with the excitation radiating dipole on the behaviors of the whispering-gallery resonance (WGR) modes in a hexagonal GaN nanowire cavity... 相似文献
Streptococcus pneumoniae is a Gram-positive pathogen with high morbidity and mortality globally but some of its pathogenesis remains unknown. Previous research has provided evidence that aminopeptidase N (PepN) is most likely a virulence factor of S. pneumoniae. However, its role in S. pneumoniae virulence and its interaction with the host remains to be confirmed. We generated a pepN gene deficient mutant strain and found that its virulence for mice was significantly attenuated as were in vitro adhesion and invasion of host cells. The PepN protein could induce a strong innate immune response in vivo and in vitro and induced secretion of IL-6 and TNF-α by primary peritoneal macrophages via the rapid phosphorylation of MAPK and PI3K/AKT signaling pathways and this was confirmed using specific pathway inhibitors. In conclusion, PepN is a novel virulence factor that is essential for the virulence of S. pneumoniae and induces host innate immunity via MAPK and PI3K/AKT signaling.
Crystal structures of enoyl-coenzyme A (CoA) isomerase from Bosea sp. PAMC 26642 (BoECI) and enoyl-CoA hydratase from Hymenobacter sp. PAMC 26628 (HyECH) were determined at 2.35 and 2.70 Å resolution, respectively. BoECI and HyECH are members of the crotonase superfamily and are enzymes known to be involved in fatty acid degradation. Structurally, these enzymes are highly similar except for the orientation of their C-terminal helix domain. Analytical ultracentrifugation was performed to determine the oligomerization states of BoECI and HyECH revealing they exist as trimers in solution. However, their putative ligand-binding sites and active site residue compositions are dissimilar. Comparative sequence and structural analysis revealed that the active site of BoECI had one glutamate residue (Glu135), this site is occupied by an aspartate in some ECIs, and the active sites of HyECH had two highly conserved glutamate residues (Glu118 and Glu138). Moreover, HyECH possesses a salt bridge interaction between Glu98 and Arg152 near the active site. This interaction may allow the catalytic Glu118 residue to have a specific conformation for the ECH enzyme reaction. This salt bridge interaction is highly conserved in known bacterial ECH structures and ECI enzymes do not have this type of interaction. Collectively, our comparative sequential and structural studies have provided useful information to distinguish and classify two similar bacterial crotonase superfamily enzymes. 相似文献
DNA‐binding protein A (dbpA) is reported to be upregulated in many cancers and associated with tumor progress. The present study aimed to investigate the role of dbpA in 5‐fluorouracil (5‐FU)‐resistant and oxaliplatin (L‐OHP)‐resistant colorectal cancer (CRC) cells. We found that 5‐FU and L‐OPH treatment promoted the expression of dbpA. Enhanced dbpA promoted the drug resistance of SW620 cells to 5‐FU and L‐OHP. DbpA knockdown inhibited cell proliferation, induced cell apoptosis, and cell cycle arrested in SW620/5‐FU and SW620/L‐OHP cells. Besides, dbpA short hairpin RNA (shRNA) enhanced the cytotoxicity of 5‐FU and L‐OHP to SW620/5‐FU and SW620/L‐OHP cells. Meanwhile, dbpA shRNA inhibited the activation of the Wnt/β‐catenin pathway that induced by 5‐FU stimulation in SW620/5‐FU cells. Activation of the Wnt/β‐catenin pathway or overexpression of checkpoint kinase 1 (Chk1) abrogated the promoting effect of dbpA downregulation on 5‐FU sensitivity of CRC cells. Importantly, downregulation of dbpA suppressed tumor growth and promoted CRC cells sensitivity to 5‐FU in vivo. Our study indicated that the knockdown of dbpA enhanced the sensitivity of CRC cells to 5‐FU via Wnt/β‐catenin/Chk1 pathway, and DbpA may be a potential therapeutic target to sensitize drug resistance CRC to 5‐FU and L‐OHP. 相似文献