PubMed · 14983170
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Elisa Izaurralde. 2004. Directing mRNA export.. https://doi.org/10.1038/nsmb0304-210
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BACKGROUND INFORMATION: In many cell lines, such as HeLa cells, STxB (Shiga toxin B-subunit) is transported from the plasma membrane to the ER (endoplasmic reticulum), via early/recycling endosomes and the Golgi apparatus, bypassing the late endocytic pathway. In human monocyte-derived macrophages and dendritic cells that are not sensitive to Shiga toxin-induced protein biosynthesis inhibition, STxB is not detectably targeted to the retrograde route and is degraded in late endosomes/lysosomes. RESULTS: We have identified B-subunit interacting proteins in HeLa cells and macrophages. In HeLa cells, the ER-localized chaperone BiP (binding protein) was co-immunoprecipitated with the B-subunit. This interaction was not observed in macrophages, consistent with our previous trafficking results. In both cell types, the B-subunit also interacted with the nucleolar protein B23. Consistently, the B-subunit could be detected on nucleoli, suggesting that it could serve to bring the holotoxin to the site of synthesis of its molecular target, rRNA. The nucleolar localization data are critically discussed. CONCLUSION: The interaction of STxB with BiP, involved in the retrotranslocation process to the cytosol and nucleolar B23, as described in this study, might be of relevance for explaining the efficiency of even low doses of Shiga toxin to inactivate cellular ribosomes, and for the use of STxB as a vector for targeting antigens to cytosolic proteasomes of the MHC I-restricted antigen presentation pathway.
Buchang-tang (BCT) has been known to suppress inflammatory and autoimmune responses. Accordingly, BCT has been clinically used in Korea as an immunomodulatory oriental medicine. Here, we report on the mechanism of action of BCT in activated MOLT-4 cells by determining the affected signaling pathways. BCT inhibits extracellular signal-regulated kinases (ERK)l/2 and p38 activation but does not interfere with phosphorylation of other mitogen-activated protein kinases, c-Jun NH2-terminal kinases 1/2 in MOLT-4 cells. The nuclear localization of nuclear factor of activated T cells 2 (NFATc) was blocked by BCT. Also, degradation of inhibitor kappaB-alpha and transactivation by nuclear factor-kappa B (NF-kappaB)/Rel A were impaired. Furthermore, interlukin (IL)-2 mRNA and protein levels were significantly diminished by BCT treatment. Our data indicate that BCT inhibits ERK1/2, p38 activation, nuclear translocation of NFATc, and NF-kappaB, resulting in diminished secretion of IL-2.
There is now compelling evidence that messenger ribonucleoprotein (mRNP) complexes after the release from the transcription/processing sites execute essentially unhindered Brownian movements in the nucleoplasm and target nuclear pore complexes (NPCs) by chance encounter. For the majority of genes expressed in eukaryotic cells, only single/few transcript copies are generated, which reinforces the stochastic nature of NPC localization. In this paper, I analyse the NPC localization by freely diffusing single mRNPs and discuss the implications for the temporal progression of gene expression and consecutive processes associated with the gene products. To this end, a walk-and-capture model is considered, assuming a spherical nuclear compartment with a partially absorbing boundary. Perfect absorption and perfect reflection mark the extreme outcomes. For this model, the closed-form analytic solution of the first-passage time probability density function (FPT p.d.f.), the mean passage time and variance have been obtained. The FPT p.d.f. enables to calculate the probability that single mRNPs localize the nuclear boundary and dock to NPCs within certain time windows. For freely moving mRNP complexes in osteosarcoma cell nuclei, a mean apparent diffusion coefficient (D) of 0.04 microm2 s(-1) (range 0.01-0.09 microm2 s(-1)) has been reported. Assuming a nuclear radius of 8 microm and D=0.04 microm2 s(-1), the position-averaged minimum mean passage time min for the considered model is 1.8 min, which presupposes perfect absorption of the mRNP complex at the first encounter with the nuclear boundary. In this case, the probability of capture in the time interval (0, min) is 0.67. In smaller sized yeast cell nuclei with a radius of 0.8 mum and D=0.04 microm2 s(-1), single diffusing mRNPs would localize an NPC within tens of seconds, rather than minutes.