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T G Morrison

Publications and source records attributed to T G Morrison.

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Intracellular processing of the vesicular stomatitis virus glycoprotein and the Newcastle disease virus hemagglutinin-neuraminidase glycoprotein.

The kinetics of intracellular transport of the vesicular stomatitis virus (VSV) glycoprotein (G) and the Newcastle disease virus (NDV) hemagglutinin-neuraminidase (HN) glycoprotein in chicken embryo cells were compared. To assay for the appearance of pulse-labelled glycoprotein at the cell surface, an antibody-binding assay was developed which allowed the precipitation of only those molecules on the outside surfaces of infected cells. Using this assay, it was found that pulse-labelled VSV G protein appeared at the cell surface with a half-time of approximately 27 min, while pulse-labelled NDV HN glycoprotein reached the cell surface with a half-time of approximately 78 min. To determine the transit time of these glycoproteins to trans-Golgi membranes, the kinetics of the acquisition of endoglycosidase H resistance was analyzed. The half-time of the transit of the G protein to the trans-Golgi membranes was found to be approximately 13 min while that of the HN glycoprotein was found to be approximately 60 min. Since the G protein migrates to the trans-Golgi membranes with a half-time of 13 min, and the cell surface with a half-time of 27 min, the half-time for the transit between the trans-Golgi membrane and the plasma membrane must be approximately 14 min. In a similar analysis, the half-time for the transit of the HN glycoprotein from the trans-Golgi membrane to the plasma membrane must be approximately 18 min, a time not significantly different from that of the G protein. Thus the difference in the kinetics of the intracellular transport of these two glycoproteins resides primarily in the transit from the rough endoplasmic reticulum to the trans-Golgi membranes. These results argue against a non-selective mechanism for the transport of plasma membrane glycoproteins to the cell surface.

Animals↗

Characterization of the soluble glycoprotein released from vesicular stomatitis virus-infected cells.

Vesicular stomatitis virus-infected Chinese hamster ovary cells release into the extracellular medium a soluble form of the vesicular stomatitis virus glycoprotein (G protein) termed Gs (Kang and Prevec, Virology 46:678-680, 1971). The properties of this molecule and the cellular site at which it is generated were characterized. By comparing the sizes and the peptide maps of the unglycosylated forms of G and Gs, we found that between 5,000 and 6,000 daltons of the carboxy-terminal end of the G protein is cleaved to generate the Gs molecule. This truncated molecule contains no fatty acid. Gs released from cells grown at 39 degrees C migrated on polyacrylamide gels slightly slower than Gs released at 30 degrees C. The unglycosylated form of Gs also showed this size difference. Furthermore, unglycosylated Gs was resolved into two species upon isoelectric focusing: the relative amounts of the two species depended upon the temperature at which infected cells were incubated. Full-sized unglycosylated virus-associated G also was resolved into two species, but the more basic form predominated at both 30 and 39 degrees C. The appearance of Gs in the extracellular medium depended upon the presence of stable, full-sized G at the cell surface. The amount of Gs released was quantitated in seven different situations in which the migration of G to the cell surface was inhibited. In all cases, the amount of Gs released was also decreased. In addition, incubation of cells surface labeled with 125I resulted in the release of 125I-labeled Gs protein, as well as full-sized G protein. These results suggest that Gs is generated primarily by proteolytic cleavage of plasma membrane-associated G at a site in the molecule just amino terminal to the membrane-spanning region of the molecule.

Animals↗

Fatty acid modification of Newcastle disease virus glycoproteins.

The fatty acid acylation of Newcastle disease virus hemagglutininin-neuraminidase and fusion glycoproteins was assayed. [3H]palmitate label was associated with cytoplasmic fusion proteins (F0 and F1) and virion-associated F1. In contrast, there was no detectable [3H]palmitate label associated with the hemagglutin-neuraminidase protein in Newcastle disease virus-infected Chinese hamster ovary cells or chicken embryo cells or in virions released from these cells. Thus, fatty acid modification may not be important for the maturation of some glycoproteins.

Acylation↗

Mutational changes in the vesicular stomatitis virus glycoprotein affect the requirement of carbohydrate in morphogenesis.

The role of carbohydrate in the morphogenesis of vesicular stomatitis virus was studied, using the antibiotic tunicamycin to inhibit glycosylation. It has been reported previously (Gibson et al., J. Biol. Chem. 254:3600-3607, 1979) that the San Juan strain of vesicular stomatitis virus requires carbohydrate for efficient migration of the glycoprotein (G) to the cell surface and for virion formation, whereas the prototype or Orsay strain of vesicular stomatitis virus is less stringent in its carbohydrate requirement at 30 degrees C. However, there are many differences between the two strains. We found that mutational changes within the G protein of the same strain of virus (prototype or Orsay) alters the requirement for carbohydrate at 30 degrees C. Group V or G protein mutants tsO45 and tsO44, like their prototype parent, did not require carbohydrate for efficient morphogenesis. In contrast, the G protein of another group V mutant, tsO110, was totally dependent upon carbohydrate addition for migration to the cell surface. Furthermore, no tsO110 particles were released in the absence of glycosylation. The wild-type prototype strain did require carbohydrate at 39.5 degrees C for insertion of the G protein into the plasma membrane and virion formation. However, a pseudorevertant of tsO44 (tsO44R), unlike the prototype parent, no longer exhibited this temperature-sensitive requirement for carbohydrate. At 39.5 degrees C in the presence of tunicamycin, tsO44R-infected cells released normal yields of particles and the unglycosylated G reached the cell surface very efficiently. In contrast to tsO110, which absolutely requires carbohydrate, mutational change in the tsO44R G protein has eliminated the requirement for carbohydrate. Thus, simple mutational changes, as opposed to many changes in the molecule, are sufficient to alter the carbohydrate requirement.

Carbohydrate Metabolism↗

Synthesis, stability, and cleavage of Newcastle disease virus glycoproteins in the absence of glycosylation.

Polypeptides synthesized in Newcastle disease virus (NDV)-infected CHO cells in the absence of glycosylation were characterized. Incorporation of either [3H]mannose of [3H]glucosamine into NDV polypeptides was inhibited to greater than 99% by the antibiotic tunicamycin. Under these conditions, infected cells synthesized proteins which comigrated on polyacrylamide gels with the viral L protein, nucleocapsid protein, membrane protein, and a polypeptide with a molecular weight of 55,000 (P55). These cells did not synthesize polypeptides with the size of the hemagglutinin-neuraminidase (HN) protein or the fusion (F0) protein. They did, however, synthesize new polypeptides with molecular weights of 75,000 (P75), 67,000 (P67), and 52,000 (P52). Peptide analysis revealed that P75 was a host cell protein whose synthesis is enhanced by tunicamycin. P67 corresponded to the unglycosylated forms of the glycoproteins were found to be relatively stable in infected cells. P55, previously thought to correspond to the cleaved form of F0, was found to be a unique viral protein which is associated with intracellular nucleocapsid structures.

Animals↗

Vesicular stomatitis virus glycoprotein is anchored to intracellular membranes near its carboxyl end and is proteolytically cleaved at its amino terminus.

The intracellular vesicular stomatitis virus glycoprotein (G) is inserted into membranes such that a small portion of one end of the molecule is exposed on the cytoplasmic surface of the endoplasmic reticulum and is susceptible to proteolytic digestion (T.G. Morrison, C.O. McQuain, and D. Simpson, J. Virol. 28:368-374). We have determined that this region of the G protein contains two methionyl tryptic peptides. The methionyl tryptic peptides of the G protein have been ordered by the use of the antibiotic pactamycin, and the two methionyl tryptic peptides removed by proteolytic digestion of intracellular G protein have been shown to be derived from the carboxyl terminal end of the protein. In addition, we have found that the unglycosylated G protein synthesized in a reticulocyte cell-free reaction migrates on polyacrylamide gels slightly slower than the unglycosylated G protein synthesized in tunicamycin-treated infected cells. We have also compared these G proteins derived from different sources by partial proteolysis (D.W. Cleveland, S.G. Fischer, M.W. Kirschner, and V.K. Laemmli, J. Biol. Chem. 252:1102-1106) and by chymotryptic peptide analysis. We have found minor differences between the two proteins consistent with the removal of 10 to 15 amino acids from the amino terminus of the intracellular G protein.

Cell Line↗

Assembly of viral membranes: nature of the association of vesicular stomatitis virus proteins to membranes.

To explore the interaction of vesicular stomatitis virus (VSV) proteins with cellular membranes, we have isolated membranes from infected cells that have been radioactively pulse-labeled. We have found conditions of isolation that result in membrane preparation which contain primarily the VSV membrane protein (M) and glycoprotein (G). Both of these proteins are very firmly attached to membranes: conditions known to release peripherally associated membrane proteins from membranes (S. Razin, Biochim, Biophys. Acta 265:241-246, 1972; S. J. Singer, Annu. Rev. Biochem. 43:805-826, 1974; S. J. Singer and G. L. Nicholson, Science 175:720-731, 1972) are ineffective in detaching either the G or the M protein. The results of trypsin digestion of these membrane fractions suggest that the M protein resides primarily on one side, the cytoplasmic side of cellular membranes, whereas the glycoprotein has been transported to the lumen of the membrane vesicle. However, we present evidence that the glycoprotein is transmembranal and that approximately 3,000 daltons of one end of the molecule is on the cytoplasmic side of the membrane. We have also found that undenatured VSV M protein contains a trypsin-resistant core with a molecular weight of 22,000. This region of the M protein is trypsin-resistant regardless of its association with membranes.

Cell Line↗

Assembly of viral membranes: maturation of the vesicular stomatitis virus glycoprotein in the presence of tunicamycin.

The role of glycosylation in the maturation of the vesicular stomatitis virus (VSV) glycoprotein was studied by use of the antibiotic tunicamycin. Tunicamycin-treated VSV-infected cells synthesize an unglycosylated form of the VSV glycoprotein (R. Leavitt, S. Schlesinger, and S. Kornfeld, J. Virol. 21:375--385, 1977). We have found that tunicamycin has no effect on the attachment of the glycoprotein to intracellular membranes or on the transport of protein to the lumen of the endoplasmic reticulum. However, tunicamycin prevented the migration of the glycoprotein from the rough endoplasmic reticulum to smooth intracellular membranes.

Cell Line↗

Assembly of viral membranes. I. Association of vesicular stomatitis virus membrane proteins and membranes in a cell-free system.

We report here an in vitro system designed to study the interactions of vesicular stomatitis virus (VSV) proteins with cellular membranes. We have synthesized the VSV nucleocapsid (N) protein, nonstructural (NS) protein, glycoprotein (G protein), and membrane (M) protein in a wheat germ, cell-free, protein-synthesizing system directed by VSV 12 to 18S RNA. When incubated at low salt concentrations with purified cytoplasmic membranes derived from Chinese hamster ovary cells, the VSV M andG proteins bind to membranes, whereas the VSV N and NS proteins do not. The VSV M protein binds to membranes in low or high divalent cation concentrations, whereas binding of significant amounts of G protein requires at least 5 mM magnesium acetate concentrations.

Cell Line↗

Synthesis of Newcastle disease virus polypeptides in a wheat germ cell-free system.

We have isolated 18S RNA from cytoplasmic extracts of Newcastle disease virus-infected Chinese hamster ovary cells and tested its ability to direct protein synthesis in extracts derived from wheat germ. The products of the cell-free reaction directed by this RNA contain polypeptides that comigrate with NP, M,F, and 47K roteins from virions. In addition, the products contain a polypeptide (67K) that migrates on polyacrylamide gels slightly faster than the HN protein from virions. Tryptic peptide analysis of the cell-free products and proteins from virions confirms their identity.

Cell Line↗

Site of synthesis of membrane and nonmembrane proteins of vesicular stomatitis virus.

Upon infection of Chinese hamster ovary cells (CHO), vesicular stomatitis (VSV) virus synthesizes two membrane proteins (the VSV glycoprotein and the VSV matrix or membrane (M) protein) and three nonmembrane proteins (the VSV nucleocapsid, the viral transcriptase, and an NS protein). We have used the VSV-infected cell as a model system for the study of the site of synthesis of these membrane and nonmembrane proteins. We have isolated VSV mRNA from free polyribosomes, membrane-bound polyribosomes, and the postribosomal supernatant, and identified the individual species of VSV mRNA present in each fraction. The mRNA which encodes the VSV glycoprotein is found exclusively on membrane-bound polyribosomes, while the mRNAs which encode the VSV, M, N, and NS proteins are found in free polyribosomes, in the membrane fraction of the cell, and in the postribosomal supernatant. Our results suggest that the VSV glycoprotein is synthesized exclusively on membrane polyribosomes, while at least some of the M, N, and NS proteins are made on free polyribosomes.

Amino Acids↗

Relationships among the polypeptides of Newcastle disease virus.

We have studied the relationships among the polypeptides of Newcastle disease virus by using both kinetic and tryptic peptide analyses. The results of our tryptic peptide analyses suggest that there are at least six unique viral polypeptides--L, HN, FO(F), NP, M, and a 47,000-dalton polypeptide. The small virion glycopolypeptide F is related to FO, a glycopolypeptide found only in infected cells. In addition, several smaller polypeptides, including a 53,000-dalton polypeptide found both in purified virions and in infected cells, are related to the nucleocaspid protein. Kinetic analysis of each viral polypeptide reveals that all of the major viral polypeptides, with the possible exception of L, are stable after an amino acid chase. A precursor-product relationship between FO and F was not demonstrable by pulse-chase experiments. Also, almost the same relative amount of F, the putative product, was present in infected cultures after either 5 or 30 min of radioisotopic labeling. These results suggest that FO is processed rapidly.

Glycopeptides↗

T7 protein synthesis in F' episome-containing cells: assignment of specific proteins to three translational groups.

Synthesis of many T7 proteins is prevented in F' episome-containing cells. In order to quantitate the degree of inhibition, we measured the activity of several T7 proteins in extracts prepared from T7-infected F(-) and F' cells and cells containing F factors mutant in phage inhibition [F'(PIF(-)2A) and F'(PIF(-)2A,2B)]. In addition, we were able to assign specific T7 proteins to the three translational units previously defined by polyacrylamide gel analysis of T7 proteins made in F(-) and episome-containing cells. After T7 infection, the presence of the wild-type F' (PIF(+)) episome led to greater than 90% inhibition of T7 DNA polymerase (product of gene 5), T7 lysozyme (gene 3.5), and gene 10 capsid protein synthesis. Nearly normal amounts of T7 RNA polymerase (gene 1) were made in these cells. T7 infection of cells containing the mutant F' (PIF(-)2A) episome led to normal synthesis of T7 RNA polymerase and T7 DNA polymerase; T7 lysozyme was synthesized at 30% of the maximal level in these cells; T7 gene 10 capsid protein synthesis was inhibited by 90%, and T7 DNA synthesis was arrested in these cells. T7 infection of cells containing the mutant F' (PIF(-)2A,2B) episome led to synthesis of normal levels of the enzymes assayed.

Cell-Free System↗

Translation of bacteriophage Q RNA by cytoplasmic extracts of mammalian cells.

Cytoplasmic extracts from Krebs II mouse ascites cells and from L cells translate messenger RNA from coliphage Qbeta with fidelity to produce products that migrate on polyacrylamide gels with those products directed by Qbeta RNA in an Escherichia coli cell-free system. The mammalian cell extracts correctly initiate and terminate Qbeta coat protein synthesis, as shown by: (i) [(3)H]lysine-and [(3)H]arginine-labeled tryptic peptides derived from the coat-sized product resemble these from authentic Qbeta coat protein, (ii) Qbeta coat (which contains methionine only at the N-terminal end) can be radioactively labeled with methionine only if the methionine is formylated, and (iii) L cell extracts directed by Qbeta am(-)11 (an amber mutant in the coat protein) RNA make no completed coat-sized material, but do make a peptide the size of the authentic amber coat fragment.

Animals↗

Comparisons of F factors and R factors: existence of independent regulation groups in F factors.

The similarity of sex pili mediated by F factors and R(fi(+)) factors and the ability of R(fi(+)) factors to control by repression the functioning of pilus genes encoded by the F factor suggested that F factors and R(fi(+)) factors are closely related. Further comparisons of the episomal properties of F factors and R(fi(+)) factors, however, indicated many differences. F factors contain information for a restriction system for phages phiII and T7. Cells containing R factors are sensitive to these phages. Furthermore, R(fi(+)) factors do not repress the F factor phiII restriction system in cells containing both an R(fi(+)) factor and an F factor. R factors and F factors are heteroimmune episomes. In addition, an R(fi(+)) factor in cells containing both an R factor and an F factor does not fully repress the expression of F-factor immunity to an incoming second F factor. R-factor and F-factor replication systems are not identical. Wild-type F-factor replication genes will complement the mutant F(ts114)lac(+) replication genes in cells containing two F factors. The F(ts114)lac(+) episome is retained when these cells are grown at 42 C; however, cells containing an R(fi(+)) factor and F(ts114)lac(+) lose the F(ts114)lac(+) when grown at 42 C, at the same rate as cells containing only the F(ts114)lac(+). The replication system of the R(fi(+)) factor will not complement the mutant F(ts114)lac(+) replication system.

Bacteriophages↗