Cell membrane Complex Enzyme Eukaryotic cell or cell component Microbe-host cell complex Microorganism or its component Other Other -- ion Pathway or action Protein Protein or gene Protein or gene complex Protein or protein complex Bacterial membrane or virus envelope Cell membrane Cytoplasm Eukaryotic cell or cell component Extracellular Golgi Golgi membrane Intercellular Intracellular Mitochondria Nucleocapsid/Cytoplasm Organelle Organelle -- Cell membrane Organelle -- Endoplasmic reticulum Organelle -- ER Organelle -- Golgi Organelle -- Golgi membrane Organelle -- Nucleus Organelle -- Phagolysosome Organelle -- Phagosome Organelle -- Ribosome Other Phagolysosome Phagosome Chaperone Defense, immunity protein Enzyme Enzyme activator Enzyme inhibitor Genomic S segment Infection Ligand binding or carrier Motor Nucleic acid binding Other Signal transducer Toxicity Transcription factor binding Transcription regulation Transporter Unknown IC Inferred by Curator IDA Inferred from Direct Assay IEA Inferred from Electronic Annotation IEP Inferred from Expression Pattern IGI Inferred from Genetic Interaction IMP Inferred from Mutant Phenotype IPI Inferred from Physical Interaction ISS Inferred from Sequence or Structural Similarity NAS Non-traceable Author Statement ND No biological Data available RCA inferred from Reviewed Computational Analysis TAS Traceable Author Statement NR Not Recorded Southern PJ Fields Virology Third Edition Volume I Arenaviridae: the viruses and their replication 1996 Compans RW The Arenaviridae Arenavirus ultrastructure and morphogenesis 1993 Burns JW, Buchmeier MJ The Arenaviridae Glycoproteins of the arenaviruses 1993 Lenz O, ter Meulen J, Klenk HD, Seidah NG, Garten W Proceedings of the National Academy of Sciences of the United States of America The Lassa virus glycoprotein precursor GP-C is proteolytically processed by subtilase SKI-1/S1P 200123 11606739 PubMed Lee KJ, de la Torre JC Arenaviruses I. The epidemiology, molecular and cell biology of arenaviruses Reverse genetics of arenaviruses 2002 Kunz S, Borrow P, Oldstone MBA Arenaviruses I. The epidemiology, molecular and cell biology of arenaviruses Receptor structure, binding, and cell entry of arenaviruses 2002 Meyer BJ, de la Torre JC, Southern PJ Arenaviruses I. The epidemiology, molecular and cell biology of arenaviruses Arenaviruses: Genomic RNAs, transcription, and replication 2002 Buchmeier MJ Arenaviruses I. The epidemiology, molecular and cell biology of arenaviruses Arenaviruses: Protein structure and function 2002 GP-1 Function: Ligand binding or carrier. GP-1 is the peripheral membrane glycoprotein. It has 4 to 11 potential N-linked glycosylation sites. The GP-1 portion of the glycoprotein spike is responsible for initial binding to cellular receptors, and antibodies directed to epitopes on GP-1 can block viral binding and neutralize viral infectivity. GP-1 has only been described for LCMV, Lassa virus, Oliveros virus, and Mobala virus.(Buchmeier)(Meyer) Alpha dystroglycan Function: Ligand binding or carrier. Alpha dystroglycan is a cell surface protein. It is a highly versatile cellular receptor for proteins of the extracellular matrix that is fundamental in cell-mediated assembly and organization of basement membranes throughout the organism. It has broad tissue distribution, is highly conserved, and is also used by Mycobacterium leprae. Guanarito virus does not bind to this receptor.(Kunz)(Meyer) Virion Function: . The arenavirus binds to the alpha-dystroglycan cell surface protein.(Kunz)(Meyer)(Buchmeier) Virion, pH 6.2 Function: . Following attachment, viruses are taken up in large (150-300 nm) smooth-walled vesicles that resemble phagocytic vesicles. This process is known as viropexis. This means that the virus membrane does not become part of the vesicle membrane.(Kunz) Virion, pH less than 6.2 Function: . Intravesicular pH drops from 6.2 to 5.0. Initial evidence that arenaviruses are taken up and undergo a pH-dependent fusion event within host cells was provided by experiments showing that infection of cells by both the Old World arenavirus LCMV and the New World arenavirus Junin could by inhibited at the entry stage by agents that raise the enodosomal pH.(Kunz) Virion with GP-2 exposed Function: . The change in pH causes GP-1 to become dissociated from the virion. It has been hypothesized that loss of GP-1 causes sequestered epitopes on GP-2 to be exposed, but the hypothetical 'fusion protein' that can mediated fusion of the virion with the vesicle membranes is currently unknown. The pH required to initiate this change is different depending upon the species.(Kunz) Virion bound to phagosome Function: . The arenavirus membrane fuses with the vesicle membrane and virion contents are released into the cytoplasm (Meyer et al., 2002). Virion contents include both the L and S segments (which vary in the ratio that they are present in. Typically it is 2:5, with S always being the more abundant), host RNAs (these include the 5 and 5.8 ribosome RNAs and tRNAs, which are not essential for virion activity), Z mRNA, Z protein, and low levels of L protein (Meyer et al., 2002).(Kunz) Genomic segment L Function: . The L RNA segment contains the L protein (polymerase) gene at the 3'-end in negative polarity and the zinc-binding (Z) protein at the 5'-end in message polarity (Peters et al., 1996).(Meyer) Genomic segment L Function: . The L RNA segment contains the L protein (polymerase) gene at the 3'-end in negative polarity and the zinc-binding (Z) protein at the 5'-end in message polarity (Peters et al., 1996).(Meyer) Antigenomic segment L Function: . Each RNA segment has an ambisence coding strategy, encoding two polypeptides in opposite orientation, separated by an intergenic region with a predicted folding of a stable hairpin structure.(Lee) L mRNA Function: . The L RNA, located at the 3' end of the L genomic segment to the intergenic noncoding region, is transcribed. The gene for L is on the 3' end of the L genomic segment and ends at an intergenic noncoding region (Meyer et al., 2002).(Buchmeier) Z mRNA Function: . The L antigenomic segment is transcribed to produce Z mRNA. The gene for Z mRNA is on the 3' end of the L antigenomic segment and ends at the intergenic noncoding region.(Meyer) L protein Function: Enzyme. The L protein is the viral RNA-dependent RNA polymerase and has a reported molecular mass of 180-250 kDa. Motifs that are common to all RNA-dependent RNA polymerases and polymerases of segmented negative strand RNA viruses, as well as two regions found only in the polymerases of arenaviruses and Bunyaviruses are conserved in arenavirus L proteins. The L protein is a component of nucleocapsids, since polymerase activity has been associated with these structures. The L protein cannot be detected until 12-24 hours post-infection, and its concentration increases dramatically during acute infection (Buchmeier, 2002).(Buchmeier) Z protein Function: Unknown. Z mRNA encodes an 11 kDa protein known as Z. The Z protein contains a RING finger motif and binds zinc. It may be directly involved with regulation of gene expression in infected cells (Meyer et al., 2002). It has been suggested that it is both a structural component of the viral nucleocapsid, and that it acts as a cofactor in viral replication and/or transcription (Lee and de la Torre, 1993)(Lee)(Meyer) Genomic segment S Function: . The S segment encodes the nucleocapsid protein (NP) in negative, antimessage sense at the 3'-end and the viral glycoprotein precursor, GP-C in message sense at the 5'-end (Peters et al., 1996).(Meyer) Genomic segment S Function: . The S segment encodes the nucleocapsid protein (NP) in negative, antimessage sense at the 3'-end and the viral glycoprotein precursor, GP-C in message sense at the 5'-end (Peters et al., 1996).(Meyer) Antigenomic segment S Function: . Each RNA segment has an ambisence coding strategy, encoding two polypeptides in opposite orientation, separated by an intergenic region with a predicted folding of a stable hairpin structure.(Lee) NP mRNA Function: . The NP RNA, located at the 3' end of the S genomic segment to the intergenic noncoding region, is transcribed. The first transcript produced by the incoming nucleoprotein complex is NP. NP mRNAs can be detected as early as 2 hours post infection.(Meyer)(Buchmeier) GP-C mRNA Function: . The GP-C RNA, located at the 3' end of the S antigenomic segment to the intergenic noncoding region, is transcribed.(Meyer) NP protein Function: . NP protein can be detected after 6-12 hours depending upon the multiplicity of infection and sensitivity of the assay (Buchmeier, 2002). NP protein accumulation either precedes replication, or the two processes are contemporary, suggesting that the first transcript produced by the incoming nucleoprotein complex is NP and that this early message is transcribed by the incoming viral RNA polymerase (Buchmeier, 2002). NP protein is the most abundant structural protein of arenaviruses with a molecular mass of 60-68 kDa. It is a major protein of nucleocapsids and associates with virion RNA to form the string of bead-like structures observed by electron microscopy. The structure of NP is consistent with a globular, basic protein with the primary function of protecting viral RNA within the cell, and it can become phosphorylated in the latter stages of acute infection. NP may be important in regulating relative levels of transcription and replication in infected cells (Meyer et al., 2002, Lee and de la Torre, 1993). Overall, the structure of NP is consistent with a globular, basic protein with the primary function of protecting the viral RNA within the cell (Buchmeier, 2002).(Buchmeier)(Meyer)(Lee) GP-C protein Function: . The primary translation product from the GP mRNA is GP-C and it is cleaved post-translationally to yield the mature glycoproteins GP-1 and GP-2.(Buchmeier) GP-C protein Function: . GP-C enters the endoplasmic reticulum and Golgi apparatus, where it is glycosylated.(Buchmeier) GP-C protein Function: . GP-C enters the endoplasmic reticulum and Golgi apparatus, where it is glycosylated.(Buchmeier) Glycosylated GP-C protein Function: . GP-C enters the endoplasmic reticulum and Golgi apparatus, where it is glycosylated.(Buchmeier) GP-1 protein Function: . Cleavage occurs 75-90 minutes after synthesis (Burns and Buchmeier, 1993). The GP-C is cleaved after conversion of high mannose oligosaccharides precursors to complex carbohydrates (Buchmeier, 2002, Burns and Buchmeier, 1993). GP-C is cleaved by a novel endoprotease, SKI-1/S1P, which, unlike furin, belongs to the pyrolysin group of subtilases and cleaves at non-basic residues. GP-C is the first viral glycoprotein known to be processed by SKI-1/S1P, and so far only three cellular proteins have been identified as substrates, the sterol regulatory element binding protein SREBP, the transcription factor ATF6, and the neurotrophic factor BDNF. GP-C is cleaved in the endoplasmic reticulum or in the cis-Golgi stacks of which SKI-1/S1P is a resident protease (Lenz et al., 2001).(Burns)(Buchmeier)(Lenz et al., 2001) GP-2 protein Function: . Cleavage occurs 75-90 minutes after synthesis (Burns and Buchmeier, 1993). The GP-C is cleaved after conversion of high mannose oligosaccharides precursors to complex carbohydrates (Buchmeier, 2002, Burns and Buchmeier, 1993). GP-C is cleaved by a novel endoprotease, SKI-1/S1P, which, unlike furin, belongs to the pyrolysin group of subtilases and cleaves at non-basic residues. GP-C is the first viral glycoprotein known to be processed by SKI-1/S1P, and so far only three cellular proteins have been identified as substrates, the sterol regulatory element binding protein SREBP, the transcription factor ATF6, and the neurotrophic factor BDNF. GP-C is cleaved in the endoplasmic reticulum or in the cis-Golgi stacks of which SKI-1/S1P is a resident protease (Lenz et al., 2001).(Burns)(Buchmeier)(Lenz et al., 2001) GP-1 protein Function: . Following glycosylation, GPC is cleaved and transported to the cell membrane. The final movement of glycoproteins to the plasma membrane is presumably mediated by a vesicular transport process, as has been observed with other enveloped viruses.(Compans) GP-2 protein Function: . Following glycosylation, GPC is cleaved and transported to the cell membrane. The final movement of glycoproteins to the plasma membrane is presumably mediated by a vesicular transport process, as has been observed with other enveloped viruses.(Compans) GP-1 and GP-2 protein Function: Ligand binding or carrier. Following glycosylation, GPC is cleaved and transported to the cell membrane. GP-1 is the peripheral membrane glycoprotein with 4 to 11 potential N-linked glycosylation sites. GP-2 homotetramers bind through ionic interaction with GP-1 homotetramers, which comprise the globular head of glycoprotein spikes.(Burns) Virion begins budding Function: . Membrane changes seen at the sites of virus budding include an increase in density of both membrane lamellae in discrete areas large enough to form a viral envelope. Surface projections were observed on the exterior of emerging virus particles. In some cells observed at late stages of infection, extensive regions of the plasma membrane were involved in virus assembly (Compans, 1993).(Compans) Virion Function: . Virions bud from the plasma membrane of acutely infected cells in regions that display thickening of the membrane and aggregation of ribosome-like structures adjacent to budding virions. The assembly process is poorly understood. Nothing is known about the assembly of viral nucleocapsids and how the interaction with the glycoproteins occurs (Southern, 1996). Moreover, there is a lack of specificity in the assembly process (Compans, 1993). Newly synthesized genomic RNAs, NP protein, and L protein are assembled into nucleocapsids intracellulary. Arenaviruses also package host-cell ribosomes into virion particles, but the number of these ribosomes is highly variable (Buchmeier, 2002).(Compans)(Southern)(Buchmeier) Hydrogen ions Function: . Following internalization of virions within vesicles, the vesicles enter the endocytic pathway and are acidified as they move through the cell. The intravesicular pH decreases from 6.2 in early endosomes to approximately 5.0 by the time the terminal compartments of the pathway (lysosomes) are reached. Fusion of the membrane of enveloped viruses with the vesicle membrane is triggered as the pH drops; the time and location of penetration of different viruses are determined by the pH dependence of the fusion activity (Kunz et al., 2002).(Kunz) SKI-1/S1P Function: Enzyme. GP-C is cleaved by a novel endoprotease, SKI-1/S1P, which, unlike furin, belongs to the pyrolysin group of subtilases and cleaves at non-basic residues. GP-C is the first viral glycoprotein known to be processed by SKI-1/S1P, and so far only three cellular proteins have been identified as substrates, the sterol regulatory element binding protein SREBP, the transcription factor ATF6, and the neurotrophic factor BDNF. GP-C is cleaved in the endoplasmic reticulum or in the cis-Golgi stacks of which SKI-1/S1P is a resident protease. It is therefore cleaved at an earlier stage of the exocytotic transport route than, for instance, the influenza virus hemagglutinin.(Lenz et al., 2001) SKI-1/S1P Function: Enzyme. GP-C is cleaved by a novel endoprotease, SKI-1/S1P, which, unlike furin, belongs to the pyrolysin group of subtilases and cleaves at non-basic residues. GP-C is the first viral glycoprotein known to be processed by SKI-1/S1P, and so far only three cellular proteins have been identified as substrates, the sterol regulatory element binding protein SREBP, the transcription factor ATF6, and the neurotrophic factor BDNF. GP-C is cleaved in the endoplasmic reticulum or in the cis-Golgi stacks of which SKI-1/S1P is a resident protease. It is therefore cleaved at an earlier stage of the exocytotic transport route than, for instance, the influenza virus hemagglutinin.(Lenz et al., 2001)