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Abstract Background TDP-43 proteinopathies are characterized by loss of nuclear TDP-43 expression and formation of C-terminal TDP-43 fragmentation and accumulation in the cytoplasm. Recent studies have shown that TDP-43 can accumulate in RNA stress granules (SGs) in response to cell stresses and this could be associated with subsequent formation of TDP-43 ubiquinated protein aggregates. However, the initial mechanisms controlling endogenous TDP-43 accumulation in SGs during chronic disease are not understood. In this study we investigated the mechanism of TDP-43 processing and accumulation in SGs in SH-SY5Y neuronal-like cells exposed to chronic oxidative stress. Cell cultures were treated overnight with the mitochondrial inhibitor paraquat and examined for TDP-43 and SG processing. Results We found that mild stress induced by paraquat led to formation of TDP-43 and HuR-positive SGs, a proportion of which were ubiquitinated. The co-localization of TDP-43 with SGs could be fully prevented by inhibition of c-Jun N-terminal kinase (JNK). JNK inhibition did not prevent formation of HuR-positive SGs and did not prevent diffuse TDP-43 accumulation in the cytosol. In contrast, ERK or p38 inhibition prevented formation of both TDP-43 and HuR-positive SGs. JNK inhibition also inhibited TDP-43 SG localization in cells acutely treated with sodium arsenite and reduced the number of aggregates per cell in cultures transfected with C-terminal TDP-43 162-414 and 219-414 constructs. Conclusions Our studies are the first to demonstrate a critical role for kinase control of TDP-43 accumulation in SGs and may have important implications for development of treatments for FTD and ALS, targeting cell signal pathway control of TDP-43 aggregation.

Oligomerization of transcription factors controls their translocation into the nucleus and DNA-binding activity. Here we present a fluorescence microscopy analysis termed pCOMB (pair correlation of molecular brightness) that tracks the mobility of different oligomeric species within live cell nuclear architecture. pCOMB amplifies the signal from the brightest species present and filters the dynamics of the extracted oligomeric population based on arrival time between two locations. We use this method to demonstrate a dependence of signal transducer and activator of transcription 3 (STAT3) mobility on oligomeric state. We find that on entering the nucleus STAT3 dimers must first bind DNA to form STAT3 tetramers, which are also DNA-bound but exhibit a different mobility signature. Examining the dimer-to-tetramer transition by a cross-pair correlation analysis (cpCOMB) reveals that chromatin accessibility modulates STAT3 tetramer formation. Thus, the pCOMB approach is suitable for mapping the impact oligomerization on transcription factor dynamics.

The c-Jun N-terminal kinases (JNKs) belong to a larger group of nitrogen-activated protein kinase family and act as stress-activated protein kinases in the livers of cycloheximide-challenged rats by phosphorylating and activating the c-Jun transcription factor. A clear insight of the intracellular actions of the JNKs and its substrates, which are often involved in activities like protein degradation, cell movement and signal transduction, is presented.

The expression of protein kinase C isoforms (PKC) is essential for cardiac ventricular development but during maturation is considerably decreased relative to protein. In human ventricles, PKC-alpha, PKC-epsilon and PKC-zeta are present, quantities of which lower with maturation. When cultured ventricular myocytes are injected with 12-O-tetradecanoylphorbol-13-acetate, activation and lowering of PKC-delta, PKC-epsilon and PKC-alpha are observed keeping the PKC-zeta unaffected.

Use of competitive binding experiments to determine whether alpha1B- and alpha1A-adrenoceptors couple with phosphoinositides (PI) hydrolysis in the isolated ventricular myocytes of adult rat hearts reveal that the 75% and 25% distribution of alpha1B- and alpha1A-1 adrenoceptor sites in the myocytes confirms that the adrenoceptors couple to PI hydrolysis. Norepinephrine, epinephrine and phenylephrine activate PI hydrolysis with or without propanol levels, while hydrolysis activation by epinephrine with 5-methyl urapidil is biphasic in nature. An irreversible alpha1B-adrenoceptor inhibitor, chloroethylclonidine, blocks the activation of PI hydrolysis by epinephrine by 35%.

Respiratory syncytial virus (RSV) is one of the leading causes of viral respiratory tract infection in infants, the elderly, and the immunocompromised worldwide, causing more deaths each year than influenza. Years of research into RSV since its discovery over 60 yr ago have elucidated detailed mechanisms of the hostpathogen interface. RSV infection elicits widespread transcriptomic and proteomic changes, which both mediate the host innate and adaptive immune responses to infection, and reflect RSV’s ability to circumvent the host stress responses, including stress granule formation, endoplasmic reticulum stress, oxidative stress, and programmed cell death. The combination of these events can severely impact on human lungs, resulting in airway remodeling and pathophysiology. The RSV membrane envelope glycoproteins (fusion F and attachment G), matrix (M) and nonstructural (NS) 1 and 2 proteins play key roles in modulating host cell functions to promote the infectious cycle. This review presents a comprehensive overview of how RSV impacts the host response to infection and how detailed knowledge of the mechanisms thereof can inform the development of new approaches to develop RSV vaccines and therapeutics. [ABSTRACT FROM AUTHOR]