PubMed · 14283758
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J S SCOTT, A D BAIN. 1965-05-15. GASTRIN.. https://pubmed.ncbi.nlm.nih.gov/14283758/
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Cytosolic internalization is a requirement for the toxicity of secretory ribonucleases. Here, we investigate the mechanism of internalization of Onconase (ONC), a toxic protein, and ribonuclease A (RNase A), a nontoxic homolog. Microscopy studies indicate that both ribonucleases readily bind to the cell surface and are internalized via acidic vesicles. Blocking dynamin-dependent endocytosis prevents transferrin internalization but does not hinder RNase A internalization. ONC and G88R RNase A, which is a toxic variant, demonstrate enhanced cytotoxicity in the absence of clathrin- and dynamin-mediated endocytosis. The cytosolic entry of ribonucleases does not require an acidic environment or transport to the ER and probably occurs from endosomes. Thus, common proteins - secretory ribonucleases - enter the cytosol by a pathway that is distinct from that of other known toxins.
BACKGROUND AND AIMS: A secretion-incompetent, highly replicating hepatitis B variant was previously found as the dominant viral population in the serum of a liver transplant recipient with severe hepatitis B reinfection. The secretion block resulted from mutations in the S protein, including the Gly145Arg substitution known to emerge under antibody to hepatitis B surface antigen immunoglobulin treatment. Here we investigated the mechanisms that allow selection of a secretion-incompetent virus as the predominant strain in the serum. METHODS: To reproduce the interaction of viral quasispecies occurring in vivo, cotransfection experiments were performed with full-length genomes containing wild-type or mutant sequences. In addition, the relevance of mutations in the common S part of the surface proteins for the competence of L and S protein to support viral secretion was studied. RESULTS: A small amount of wild-type virus or of a wild-type S protein-expressing variant rescued secretion of the defective mutant. In the secreted virions, the high-replicating mutant genome was predominant. Selection of the defective mutant was further supported by a transdominant negative effect of mutant S protein on wild-type virion secretion. In contrast, mutant L protein with the same c-terminal mutations as mutant S protein efficiently supported virion formation and secretion. CONCLUSIONS: Interaction of the variant with a small amount of wild-type virus can reverse its secretion-defective phenotype. Mutations in the common region of S and L protein have different consequences for the ability of the envelope proteins to support virion assembly and secretion.
The overexpression of certain membrane proteins is accompanied by a striking proliferation of intracellular membranes. One of the best characterized inducers of membrane proliferation is the 180-kD mammalian ribosome receptor (p180), whose expression in yeast results in increases in levels of mRNAs encoding proteins that function in the secretory pathway, and an elevation in the cell's ability to secrete proteins. In this study we demonstrate that neither the unfolded protein response nor increased transcription accounts for membrane proliferation or the observed increase in secretory pathway mRNAs. Rather, p180-induced up-regulation of certain secretory pathway transcripts is due to a p180-mediated increase in the longevity of these mRNA species, as determined by measurements of transcriptional activity and specific mRNA turnover. Moreover, we show that the longevity of mRNA in general is substantially promoted through the process of its targeting to the membrane of the endoplasmic reticulum. With respect to the terminal differentiation of secretory tissues, results from this model system provide insights into how the expression of a single protein, p180, could result in substantial morphological and functional changes.