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PubMed2004

Cell membrane proteins and quasispecies compartmentalization of CSF and plasma HIV-1 from aids patients with neurological disorders.

Cell membrane protein (CMP) profile of HIV-1 from cerebrospinal fluid (CSF) and plasma of five AIDS patients with neurologic disorders was analyzed and compared with viral quasispecies composition in these body compartments. To this aim, paired CSF and plasma samples from AIDS subjects with HIV-related neurological diseases (three HIV-1 encephalopaty (HIVE) and two primary CNS lymphoma (PCNSL)) underwent immobilized antibody capture (IAC) assay to determine the profile of CMP acquired by HIV-1. The considered CMPs were CD45RO, CD26, CD36, glut-R, N-CAM, VCAM-1, ELAM-1, CD44 and CD58, representing lymphomonocyte, neuronal and adhesion molecules. Cloning and sequencing of env and gag regions was performed to predict coreceptor usage and to analyze quasispecies compartmentalization. The results indicated that CD44 and CD58 were the most represented molecules on HIV-1 from CSF, whereas CD36 was the most abundant molecule on plasma HIV-1. V3 env aminoacidic sequences and net charge were consistent with M-R5 phenotype in all CSF and in most plasma clones. The degree of genetic heterogeneity (both complexity and diversity) in p17 gag was significantly lower in CSF-HIV than that in plasma-HIV for three patients, higher for one patient, and not significantly different for one patient, suggesting compartmentalization for all but the latter patient. When considering the pattern of CMP, the most abundant CMP observed in HIV from plasma and CSF was different in patients showing compartmentalization, while was the same in the patient without significant differences in CSF and plasma quasispecies. In conclusion, the present data on CMP pattern, V3 loop aminoacidic signature and genetic heterogeneity of HIV-1 quasispecies from CSF and plasma of HIVE patients, are consistent with a compartmentalized virus replication, at least in some patients, and with a possible different source of HIV in the two body sites, even though in a context of a largely prevalent M-R5 phenotype.

AIDS Dementia Complex↗
PubMed1992

Design of yeast-secreted albumin derivatives for human therapy: biological and antiviral properties of a serum albumin-CD4 genetic conjugate.

Due to its remarkably long half-life, together with its wide in vivo distribution and its lack of enzymatic or immunological functions, human serum albumin (HSA) represents an optimal carrier for therapeutic peptides/proteins aimed at interacting with cellular or molecular components of the vascular and interstitial compartments. As an example, we designed a genetically engineered HSA-CD4 hybrid aimed at specifically blocking the entry of the human immunodeficiency virus into CD4+ cells. In contrast with CD4, HSA-CD4 is correctly processed and efficiently secreted by Kluyveromyces yeasts. In addition, its CD4 moiety exhibits binding and antiviral in vitro properties similar to those of soluble CD4. Finally, the elimination half-life of HSA-CD4 in a rabbit experimental model is comparable to that of control HSA and 140-fold higher than that of soluble CD4. These results indicate that the genetic fusion of bioactive peptides to HSA is a plausible approach toward the design and recovery of secreted therapeutic HSA derivatives with appropriate pharmacokinetic properties.

Animals↗
PubMed1991

Differentiation of acid-pH-dependent and -nondependent entry pathways for mouse hepatitis virus.

Early events of infection of MHV were studied in comparison with those of VSV, which is known to enter cells by an endocytic pathway. Treatment of mouse L-2 fibroblasts with ammonium chloride, chloroquine, or dansylcadaverine inhibited infection of MHV to a much lesser degree than that of VSV, suggesting a relatively minor role for the endocytic pathway and functional endosomes in MHV infection. Endocytosis of MHV and VSV into L-2 cells was assayed by the recovery of infectious (i.e., not uncoated) viruses from homogenates of cells harvested within the first few minutes of infection (and treated with protease to remove surface-bound virus). The results thus suggest that while a small proportion of the MHV inoculum is internalized by endocytosis, productive infection does not depend on functional endocytosis as utilized by VSV. Studies on direct virion-mediated cell fusion showed that MHV can induce fusion at pH 7.4, whereas VSV causes fusion at pH 5.0. Taken together, the above results suggest that MHV enters L-2 cells predominantly by membrane fusion with a non-acidified compartment such as the plasma membrane, endocytic vesicles, or endosomes (prior to their acidification). Results obtained from cell lines which differed in permissiveness to MHV infection suggested that the ability to support MHV infection does not correlate with endocytosis. Rather, nonpermissive cells, such as rat astrocytoma (C-6) and Vero cells, showed higher levels of recoverable internalized MHV than did fully permissive L-2 cells. Cells which are normally nonpermissive to MHV, could be rendered MHV-susceptible by PEG-induced fusion of cell surface-bound virus. Such PEG-mediated susceptibility to MHV infection was insensitive to inhibition by ammonium chloride, supporting the idea that host cell restriction of MHV infection in C-6 and Vero cells may be due to a block in nonendosomal membrane fusion. Thus endocytic internalization of MHV, which clearly occurs in a variety of cells, does not guarantee productive infection.

Acids↗
PubMed2006

Extracellular matrix of the developing ovarian follicle.

There are many different types of extracellular matrices in the different follicle compartments. These have different roles in follicle development and atresia, and they change in composition during these processes. This review focuses on basal lamina matrix in particular, and considers follicular fluid, the newly identified focimatrix, and thecal matrices. When follicles commence growing, the follicular basal lamina changes in its composition from containing all six alpha chains of type IV collagen to only alpha1 and alpha2. Perlecan and nidogen-1 and -2 subsequently become components of the follicular basal lamina, and there is an increase in the amount of laminin chains alpha1, beta2, and gamma1, in the bovine at least. Late in follicular development and on atresia some follicles contain laminin alpha2. On atresia the follicular basal lamina is not degraded, as occurs in ovulation, but can be breached by cells from the thecal layer when it is not aligned by granulosa cells. A novel type of basal lamina-like matrix, called focimatrix (abbreviated from focal intraepithelial matrix), develops between the cells of the membrana granulosa as aggregates of basal lamina material. It does not envelop cells and so cannot perform functions of basal lamina as currently understood. It is hypothesized that focimatrix assists or initiates depolarization of the membrana granulosa necessary for the transformation into luteal cells. The largest osmotically active molecules in follicular fluid are hyaluronan and chondroitin sulfate proteoglycans, including versican and inter-alpha trypsin inhibitor. It has been suggested that these might be responsible for the formation of follicular fluid by creating an osmotic gradient across the follicular wall. The formation, development, and then either ovulation or regression of follicles requires considerable tissue remodeling, cellular replication, and specialization. The expectation of researchers is that extracellular matrix will be intimately involved in many of these processes. Much research has focused in identifying the components of extracellular matrix and associated developmental changes. We review the components of extracellular matrix associated with follicular development, including the basal lamina, focimatrix, follicular fluid, and matrix of the thecal layers.

Animals↗
PubMed2002

Retrieval of human cytomegalovirus glycoprotein B from cell surface is not required for virus envelopment in astrocytoma cells.

Human cytomegalovirus (HCMV) is a prototypic member of the betaherpesvirus family. The HCMV virion is composed of a large DNA genome encapsidated within a nucleocapsid, which is wrapped within an inner proteinaceous tegument and an outer lipid envelope containing viral glycoproteins. Although genome encapsidation clearly occurs in the nucleus, the subsequent steps in the virion assembly process are unclear. HCMV glycoprotein B (gB) is a major component of the virion envelope that plays a critical role in virus entry and is essential for the production of infectious virus progeny. The aim of our present study was to identify the secretory compartment to which HCMV gB was localized and to investigate the role of endocytosis in mediating gB localization and HCMV biogenesis. We show that HCMV gB is localized to the trans-Golgi network (TGN) in HCMV-infected cells and that gB contains all of the trafficking information necessary for TGN localization. Endocytosis of gB was shown to play a role in mediating TGN localization of gB and in targeting of the protein to the site of virus envelopment. However, inhibition of endocytosis with a dominant-negative dynamin I molecule did not affect the production of infectious virus. These observations indicate that, although endocytosis is involved in the trafficking of gB to the site of glycoprotein accumulation in the TGN, endocytosis of gB is not required for the production of infectious HCMV.

Astrocytoma↗
PubMed1991

Growth and cell kinetics of human hair papilla cells in vitro. An autoradiographic and flow cytometric study.

Hair papilla, a distinct specialized dermal compartment, plays a fundamental role in the biology of hair growth. Recently some attention has been focused on hair papilla cells (HPC) as possible targets for drugs influencing the hair growth. Isolation and cultivation of the HPC facilitates screening for such drugs. In the present work, growth and cell kinetics of human occipital scalp follicle HPC have been studied in vitro. HPC grow according to a Gompertz function, i.e. with considerable growth delay long before becoming confluent cultures, due probably to elongation of the potential doubling time (Tpot) and to a parallel increasing cell loss rate. The [3H]dT labelling index of the HPC strongly depends on the age of the subculture; the cycle time being about 4 days. A potential doubling time of about 93 h, indicative of growth fraction (GF) = 1, and a duration of S phase and G2 + M phase of about 8 h each were found by the combined application of continuous labelling with [3H]dT and DNA flow cytometry.

Adult↗
PubMed1999

Baculovirus expression system cells expressing v-myb oncogene: the distribution of RNA and DNA in specific nuclear compartments with respect to structures interacting with anti-v-Myb antibody.

The distribution of RNA, total DNA and newly synthesized DNA within nucleoli-like structures in insect cells overexpressing v-myb oncogene was investigated. Three types of these structures which revealed interaction with anti-v-Myb oncoprotein antibody were found at the ultrastructural level. Specific staining by toluidine blue at pH 5.2 showed the presence of RNA in these nucleoli-like structures. To detect total DNA, the in situ terminal deoxynucleotidyl transferase-immunogold technique was used. In addition to an expected labeling of host condensed chromatin, the labeling of the three types of nucleoli-like structures differed from each other. While the compact (type I) and ring-shaped (type II) nucleoli-like structures were labeled only on their periphery and in the proximity of baculovirus particles that interacted with them, the structures with an appearance of nucleolonemas (type III) were labeled strongly. Incorporation of 5-bromo-2-deoxyuridine, in spite of a poor labeling of newly synthesized DNA, confirmed these results. We suggest that the nucleoli-like structures of type I and II are of nucleolar origin. The type III more likely represents virogenic stroma or viral DNA storage site.

Animals↗
PubMed1999

Three-dimensional visualization of transcription sites and their association with splicing factor-rich nuclear speckles.

Transcription sites are detected by labeling nascent transcripts with BrUTP in permeabilized 3T3 mouse fibroblasts followed by laser scanning confocal microscopy. Inhibition and enzyme digestion studies confirm that the labeled sites are from RNA transcripts and that RNA polymerase I (RP I) and II (RP II) are responsible for nucleolar and extranucleolar transcription, respectively. An average of 2,000 sites are detected per nucleus with over 90% in the extranucleolar compartment where they are arranged in clusters and three-dimensional networklike arrays. The number of transcription sites, their three-dimensional organization and arrangement into functional zones (Wei et al. 1998) is strikingly maintained after extraction for nuclear matrix. Significant levels of total RP II mediated transcription sites (45%) were associated with splicing factor-rich nuclear speckles even though the speckles occupied <10% of the total extranucleolar space. Moreover, the vast majority of nuclear speckles (>90%) had moderate to high levels of associated transcription activity. Transcription sites were found along the periphery as well as inside the speckles themselves. These spatial relations were confirmed in optical sections through individual speckles and after in vivo labeling of nascent transcripts. Our results demonstrate that nuclear speckles and their surrounding regions are major sites of RP II-mediated transcription in the cell nucleus, and support the view that both speckle- and nonspeckle-associated regions of the nucleus contain sites for the coordination of transcription and splicing processes.

3T3 Cells↗
PubMed1991

Ganglioside or sialic acid attenuates ethanol-induced decrements in locomotion, nose-poke exploration, and anxiety, but not body temperature.

1. This laboratory has previously reported that pretreatment with ganglioside, or even with its constituent, sialic acid (SA), can attenuate certain intoxicating effects of ethanol. It was important to see if these findings could be replicated, particularly by using other measures of ethanol effects. Herein we report that pretreatment with either gangliosides or SA attenuated ethanol-induced decrements in locomotion, nose-poke exploration, and anxiety, but not body temperature. 2. An ethanol dose of 4 gm/kg caused a temperature drop of about 3 degrees C, which was unaffected by any pretreatment. The onset to sleep, however, was delayed an average of 18 or 36 secs in mice pretreated with ganglioside or SA, respectively. Ethanol-only (4 gm/kg) depressed mean cumulative locomotor activity to 31% of normal, whereas the depression was 83% of normal with beef brain ganglioside pretreatment. At 2 gm/kg ethanol alone decreased nose poking in a hole-board test to 29% of normal, but the depression was only 55-63% of normal with SA or ganglioside pretreatment. In a staircase climbing anxiety test, this dose of ethanol had no effect by itself, but both ganglioside and SA pre-treatment increased climbing by 22%. Ethanol did depress rearing to only 11% of normal, whereas rearing was 51 and 99% of normal with SA and ganglioside pretreatment, respectively. In a dark-preference test, ethanol-only caused mice to spend 64% of the time in the light, compared to 31% for controls. Time in the light was only 39 and 46% with ganglioside and SA pretreatment, respectively. 3. Blood levels of ethanol were not significantly affected by pretreatment. 4. When given alone, gangliosides significantly stimulated locomotion and staircase climbing. SA significantly decreased rearing in the staircase test. Both gangliosides and SA tended to increase nose poking, number of crossings in the dark-preference test, and time in a lighted compartment. Thus, it is possible that some of the attenuation of intoxication is attributable to non-specific stimulant properties of gangliosides and SA.

Animals↗
PubMed2003

Role of PACS-1 in trafficking of human cytomegalovirus glycoprotein B and virus production.

The final envelopment of herpesviruses during assembly of new virions is thought to occur by the budding of core viral particles into a late secretory pathway organelle, the trans-Golgi network (TGN), or an associated endosomal compartment. Several herpesvirus envelope glycoproteins have been previously shown to localize to the TGN when expressed independently from other viral proteins. In at least some cases this TGN localization has been shown to be dependent on clusters of acidic residues within their cytoplasmic domains. Similar acidic cluster motifs are found in endogenous membrane proteins that also localize to the TGN. These acidic cluster motifs interact with PACS-1, a connector protein that is required for the trafficking of proteins containing such motifs from endosomes to the TGN. We show here that PACS-1 interacts with the cytoplasmic domain of the HCMV envelope glycoprotein B (gB) and that PACS-1 function is required for normal TGN localization of HCMV gB. Furthermore, inhibition of PACS-1 activity in infected cells leads to a decrease in HCMV titer, whereas an increase in expression of functional PACS-1 leads to an increase in HCMV titer, suggesting that PACS-1 is required for efficient production of HCMV.

Carrier Proteins↗
PubMed1999

The effects of methylglyoxal-bis(guanylhydrazone) on spermine binding and transport in liver mitochondria.

This study evaluated the effect of the anticancer drug methylglyoxal-bis(guanylhydrazone) (MGBG) on the binding of the polyamine spermine to the mitochondrial membrane and its transport into the inner compartment of this organelle. Spermine binding was studied by applying a new thermodynamic treatment of ligand-receptor interactions (Di Noto et al., Macromol Theory Simul 5: 165-181, 1996). Results showed that MGBG inhibited the binding of spermine to the site competent for the first step in polyamine transport; the interaction of spermine with this site, termed S1, also mediates the inhibitory effect of the polyamine on the mitochondrial permeability transition (Dalla Via et al., Biochim Biophys Acta 1284: 247-252, 1996). In the presence of 1 mM MGBG, the binding capacity and affinity of this site were reduced by about 2.6-fold; on the contrary, the binding capacity of the S2 site, which is most likely responsible for the internalization of cytoplasmic proteins (see Dalla Via et al., reference cited above), increased by about 1.3-fold, and its binding affinity remained unaffected. MGBG also inhibited the initial rate of spermine transport in a dose-dependent manner by establishing apparently sigmoidal kinetics. Consequently, the total extent of spermine accumulation inside mitochondria was inhibited. This inhibition in transport seems to reflect a conformational change at the level of the channel protein constituting the polyamine transport system, rather than competitive inhibition at the inner active site of the channel, thereby excluding the possibility that the polyamine and drug use the same transport pathway. Furthermore, it is suggested that, in the presence of MGBG, the S2 site is able to participate in residual spermine transport. MGBG also strongly inhibits deltapH-dependent spermine efflux, resulting in a complete block in the bidirectional flux of the polyamine and its sequestration inside the matrix space. The effects of MGBG on spermine accumulation are consistent with in vivo disruption of the regulator of energy metabolism and replication of the mitochondrial genome.

Animals↗
PubMed2003

HIV Gag mimics the Tsg101-recruiting activity of the human Hrs protein.

The HIV-1 Gag protein recruits the cellular factor Tsg101 to facilitate the final stages of virus budding. A conserved P(S/T)AP tetrapeptide motif within Gag (the "late domain") binds directly to the NH2-terminal ubiquitin E2 variant (UEV) domain of Tsg101. In the cell, Tsg101 is required for biogenesis of vesicles that bud into the lumen of late endosomal compartments called multivesicular bodies (MVBs). However, the mechanism by which Tsg101 is recruited from the cytoplasm onto the endosomal membrane has not been known. Now, we report that Tsg101 binds the COOH-terminal region of the endosomal protein hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs; residues 222-777). This interaction is mediated, in part, by binding of the Tsg101 UEV domain to the Hrs 348PSAP351 motif. Importantly, Hrs222-777 can recruit Tsg101 and rescue the budding of virus-like Gag particles that are missing native late domains. These observations indicate that Hrs normally functions to recruit Tsg101 to the endosomal membrane. HIV-1 Gag apparently mimics this Hrs activity, and thereby usurps Tsg101 and other components of the MVB vesicle fission machinery to facilitate viral budding.

Cell Line↗
PubMed2002

Caveolar endocytosis of simian virus 40 is followed by brefeldin A-sensitive transport to the endoplasmic reticulum, where the virus disassembles.

Simian virus 40 (SV40) enters cells by atypical endocytosis mediated by caveolae that transports the virus to the endoplasmic reticulum (ER) instead of to the endosomal-lysosomal compartment, which is the usual destination for viruses and other cargo that enter by endocytosis. We show here that SV4O is transported to the ER via an intermediate compartment that contains beta-COP, which is best known as a component of the COPI coatamer complexes that are required for the retrograde retrieval pathway from the Golgi to the ER. Additionally, transport of SV40 to the ER, as well as infection, is sensitive to brefeldin A. This drug acts by specifically inhibiting the ARF1 GTPase, which is known to regulate assembly of COPI coat complexes on Golgi cisternae. Moreover, some beta-COP colocalizes with intracellular caveolin-1, which was previously shown to be present on a new organelle (termed the caveosome) that is an intermediate in the transport of SV40 to the ER (L. Pelkmans, J. Kartenbeck, and A. Helenius, Nat. Cell Biol. 3:473-483, 2001). We also show that the internal SV40 capsid proteins VP2 and VP3 become accessible to immunostaining starting at about 5 h. Most of that immunostaining overlays the ER, with some appearing outside of the ER. In contrast, immunostaining with anti-SV40 antisera remains confined to the ER.

Animals↗
PubMed1987

Comparative O2-. responses of lung macrophages and blood phagocytic cells in the rat. Possible relevance to IgA immune complex induced lung injury.

IgA immune complex-induced lung injury in the rat is oxygen radical mediated and partially complement-dependent but develops fully after neutrophil depletion. The extent to which monocytes, lung interstitial macrophages, and alveolar macrophages may be involved in the development of lung injury in this model is unclear. To further understand the pathogenesis of IgA lung injury, we have examined the capacity of phagocytic cells isolated from different anatomic compartments of the lung to produce toxic oxygen-derived metabolites. [3H]Thymidine pulse labeling and autoradiography as well as in vivo phagocytosis studies were used to distinguish macrophages isolated from the alveolar and interstitial compartments. Lung interstitial macrophages were characterized ultrastructurally, cytochemically, and functionally. Interstitial macrophages were relatively uniform in size, had blunt pseudopodia, and contained almost no intracytoplasmic lamellar inclusions compared to alveolar macrophages. Similar to monocytes and alveolar macrophages, interstitial macrophages contained nonspecific esterase activity and exhibited the capacity to phagocytize latex and opsonized zymosan particles. Lung interstitial and alveolar macrophages incubated with IgA immune complexes, IgG immune complexes, or phorbol ester (PMA) produced similar amounts of O2-. in a dose-dependent manner. In contrast, peripheral blood neutrophils responded to IgG immune complexes and PMA but not to IgA immune complexes. Monocytes produced a small amount of O2-. in response to PMA but almost no O2-. in response to IgA or IgG immune complexes. These data are consistent with recent in vivo studies which indicate that IgA immune complex lung injury is neutrophil independent. The data provide direct in vitro evidence that lung interstitial and alveolar macrophages produce O2-. following incubation with PMA, IgA, or IgG immune complexes and may therefore contribute to the development of oxygen radical mediated lung injury.

Animals↗
PubMed1988

Inhibition of DNA polymerization and DNA transcription to RNA by seminal plasma peptides.

An oligopeptide fraction purified from the extracellular compartment of bull semen and strongly interacting with DNA was shown to hinder mononucleotide polymerizations to DNA and RNA in vitro. The fraction, collectively called seminal plasma inhibitor, was active in the endogenous DNA and RNA polymerase reactions of the nuclei from rat hepatocytes and in the analogous nucleotide polymerizations catalyzed by purified enzymes of bacterial origin. The type of the induced inhibition was studied using the RNA polymerase from Escherichia coli as a representative nucleotidyl transferase. In the enzymatic polycondensation of mononucleotides, the seminal plasma inhibitor appeared to exert its effect mainly by a competitive inhibition for the utilization of DNA templates without specificity with respect to the source and the base sequence of DNA. Concavities of the plots of V0/Vi versus the amounts of inhibitor in the nucleotide polymerizing reactions and of the Dixon plots in the assays of RNA polymerase from E. coli suggested that the isolated oligopeptide fraction contained more than one active molecular species with differential effects at low and high doses. Preliminary results on the microheterogeneity of the seminal plasma inhibitor supported this contention.

Amino Acids↗
PubMed1982

Endocytosis of enveloped animal viruses.

After attaching to the cell surface, virus particles are rapidly internalized by endocytosis and channelled into the lysosomal compartment. The endocytosis occurs by a pinocytic process involving coated pits and coated vesicles. Intermediate pre-lysosomal vacuoles, termed endosomes, are recognized as a part of the intracellular pathway. Our studies have shown that for several of the enveloped viruses (toga viruses, orthomyxoviruses and rhabdoviruses) the endocytic pathway is essential for productive infection. In these cases the viral genome penetrates from the lysosomes where the virus membrane fuses with the lysosomal membrane. The low pH in the lysosomes triggers membrane fusion by causing a conformational change in the virus spike glycoproteins, which results in the expression of potent fusion activity. As a result of the fusion reaction the nucleocapsids are transferred into the cytoplasm. In this paper we review some work in which Semliki Forest virus (SFV) has been used to probe the adsorptive endocytosis pathway in baby hamster kidney (BHK-21) cells. In addition, we present new data on the kinetics by which the contents of the endocytic vacuoles become acidified. In these studies the pH-dependent penetration by SFV has been used as an indicator of pH.

Ammonium Chloride↗
PubMed2000

Cutting edge: selective IL-18 requirements for induction of compartmental IFN-gamma responses during viral infection.

Optimal protective effects for defense against infection require orchestration of immune responses spanning multiple host compartments and divergent local regulation at particular sites. During murine cytomegalovirus infections known to target spleen and liver, IL-12-induced IFN-gamma from NK cells is crucial for resistance. However, the roles for IL-18 and/or IL-12 in regulating hepatic IFN-gamma responses, as compared with systemic or splenic responses, have not been defined. In this report, mice genetically deficient in either IL-18 or IL-12p35 exhibited up to 95% reductions in systemic and splenic IFN-gamma responses. Surprisingly, IFN-gamma responses were preserved in the livers of IL-18-deficient, but not IL-12p35-deficient, mice. Cytokine requirements for host survival also differed. Under conditions where mice lacking IL-12p35 exhibited 100% mortality, those lacking IL-18 survived. Taken together, our results delineate contrasting compartmental requirements for IL-18 and suggest that preservation of local, hepatic IFN-gamma production is critical for host defense during murine cytomegalovirus challenge.

Animals↗
PubMed2024

Rabies Virus Phosphoprotein Exhibits Thermoresponsive Phase Separation with a Lower Critical Solution Temperature.

Rabies virus (RABV) generates membrane-less liquid organelles (Negri bodies) in the cytoplasm of its host cell, where genome transcription and replication and nucleocapsid assembly take place, but the mechanisms of their assembly and maturation remain to be explained. An essential component of the viral RNA synthesizing machine, the phosphoprotein (P), acts as a scaffold protein for the assembly of these condensates. This intrinsically disordered protein forms star-shaped dimers with N-terminal negatively charged flexible arms and C-terminal globular domains exhibiting a large dipole moment. Our study shows that in vitro self-association of RABV P drives a complex thermoresponsive phase separation with a lower critical solution temperature. Protein dimers assemble already below the saturation concentration, and condensation is driven by attractive conformation-specific interactions leading to reentrant liquid phase separation over a narrow range of salt concentration. We propose a minimal molecular model in which P can adopt three limit conformational states and the disordered N-terminal arms control the interactions between giant dipoles that is consistent with our observations.

Rabies virus↗