scholarly journals Restriction of Retroviral Replication by Tetherin/BST-2

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Jason Hammonds ◽  
Jaang-Jiun Wang ◽  
Paul Spearman

Tetherin/BST-2 is an important host restriction factor that limits the replication of HIV and other enveloped viruses. Tetherin is a type II membrane glycoprotein with a very unusual domain structure that allows it to engage budding virions and retain them on the plasma membrane of infected cells. Following the initial report identifying tetherin as the host cell factor targeted by the HIV-1 Vpu gene, knowledge of the molecular, structural, and cellular biology of tetherin has rapidly advanced. This paper summarizes the discovery and impact of tetherin biology on the HIV field, with a focus on recent advances in understanding its structure and function. The relevance of tetherin to replication and spread of other retroviruses is also reviewed. Tetherin is a unique host restriction factor that is likely to continue to provide new insights into host-virus interactions and illustrates well the varied ways by which host organisms defend against viral pathogens.

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Kylie H. Van der Hoek ◽  
Nicholas S. Eyre ◽  
Byron Shue ◽  
Onruedee Khantisitthiporn ◽  
Kittirat Glab-Ampi ◽  
...  

2021 ◽  
Author(s):  
H Stewart ◽  
KH Johansen ◽  
N McGovern ◽  
R Palmulli ◽  
GW Carnell ◽  
...  

AbstractThe antiviral restriction factor, tetherin, blocks the release of several different families of enveloped viruses, including the Coronaviridae. Tetherin is an interferon-induced protein that forms parallel homodimers between the host cell and viral particles, linking viruses to the surface of infected cells and inhibiting their release. We demonstrate that SARS-CoV-2 downregulates tetherin to aid its release from cells, and investigate potential proteins involved in this process. Loss of tetherin from cells caused an increase in SARS-CoV-2 viral titre. We find SARS-CoV-2 spike protein to be responsible for tetherin downregulation, rather than ORF7a as previously described for the 2002-2003 SARS-CoV. We instead find ORF7a to be responsible for Golgi fragmentation, and expression of ORF7a in cells recapitulates Golgi fragmentation observed in SARS-CoV-2 infected cells.HighlightsSARS-CoV-2 downregulates the host restriction factor, tetherin.Tetherin loss enhances viral titre and spread.SARS-CoV-2 ORF7a protein does not downregulate tetherin, but instead induces Golgi fragmentation.Tetherin downregulation is mediated by SARS-CoV-2 spike.


Pathogens ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 6
Author(s):  
Chathura D. Suraweera ◽  
Mark G. Hinds ◽  
Marc Kvansakul

Apoptosis is a form of cellular suicide initiated either via extracellular (extrinsic apoptosis) or intracellular (intrinsic apoptosis) cues. This form of programmed cell death plays a crucial role in development and tissue homeostasis in multicellular organisms and its dysregulation is an underlying cause for many diseases. Intrinsic apoptosis is regulated by members of the evolutionarily conserved B-cell lymphoma-2 (Bcl-2) family, a family that consists of pro- and anti-apoptotic members. Bcl-2 genes have also been assimilated by numerous viruses including pox viruses, in particular the sub-family of chordopoxviridae, a group of viruses known to infect almost all vertebrates. The viral Bcl-2 proteins are virulence factors and aid the evasion of host immune defenses by mimicking the activity of their cellular counterparts. Viral Bcl-2 genes have proved essential for the survival of virus infected cells and structural studies have shown that though they often share very little sequence identity with their cellular counterparts, they have near-identical 3D structures. However, their mechanisms of action are varied. In this review, we examine the structural biology, molecular interactions, and detailed mechanism of action of poxvirus encoded apoptosis inhibitors and how they impact on host–virus interactions to ultimately enable successful infection and propagation of viral infections.


2021 ◽  
Author(s):  
Zhaolong Li ◽  
Xu Yang ◽  
Zhilei Zhao ◽  
Xin Liu ◽  
Wenyan Zhang

The host restriction factor APOBEC3G (A3G) presents extensively inhibition on a variety of viruses, including retroviruses, DNA and RNA viruses. Our recent study showed that A3G inhibits enterovirus 71 (EV71) and coxsackievirus A16 (CA16) via competitively binding 5’UTR with the host protein poly(C)-binding protein 1 (PCBP1) that is required for multiple EVs replication. However, in addition to EV71 and CA16, whether A3G inhibits other EVs has not been investigated. Here, we demonstrate that A3G could inhibit EVD68 replication, which needs PCBP1 for its replication, but not CA6 that PCBP1 is dispensable for CA6 replication. Further investigation revealed that nucleic acid binding activity of A3G is required for EVD68 restriction, which is similar to the mechanism presented in EV71 restriction. Mechanistically, A3G competitively binds to the cloverleaf (1–123) and the stem-loop IV (234-446) domains of EVD68 5’UTR with PCBP1, thereby inhibiting the 5'UTR activity of EVD68, whereas A3G doesn’t interact with CA6 5’UTR results in no effect on CA6 replication. Moreover, non-structural protein 2C encoded by EVD68 overcomes A3G suppression through inducing A3G degradation via the autophagy-lysosome pathway. Our finding revealed that A3G might have broad spectrum antiviral activity against multiple EVs through the general mechanism, which might provide important information for the development of anti-EVs strategy. Importance As the two major pathogens causing hand, food, and mouth disease (HFMD), EV71 and CA16 attract more attention for the discovery of pathogenesis, the involvement of cellular proteins and so on. However, other EVs such as CA6 or EVD68 constantly occurred sporadic or might spread widely in recent years worldwide. Therefore, more information related to these EVs needs to be further investigated so as to develop broad-spectrum anti-EVs inhibitor. In this study, we first reveal that PCBP1 involved in PV and EV71 virus replication, also is required for the replication of EVD68 but not CA6. Then we found that the host restriction factor A3G specifically inhibits the replication of EVD68 but not CA6 via competitively binding to the 5’UTR of EVD68 with PCBP1. Our findings broaden the knowledge related to EVs replication and the interplay between EVs and host factors.


2013 ◽  
Vol 14 (3) ◽  
pp. 229-231 ◽  
Author(s):  
Michael S. Diamond ◽  
John W. Schoggins

2019 ◽  
Vol 48 (1) ◽  
pp. 304-315 ◽  
Author(s):  
Guifang Chen ◽  
Li-Chung Ma ◽  
Shanshan Wang ◽  
Ryan L Woltz ◽  
Emily M Grasso ◽  
...  

Abstract Influenza A viruses cause widespread human respiratory disease. The viral multifunctional NS1 protein inhibits host antiviral responses. This inhibition results from the binding of specific cellular antiviral proteins at various positions on the NS1 protein. Remarkably, binding of several proteins also requires the two amino-acid residues in the NS1 N-terminal RNA-binding domain (RBD) that are required for binding double-stranded RNA (dsRNA). Here we focus on the host restriction factor DHX30 helicase that is countered by the NS1 protein, and establish why the dsRNA-binding activity of NS1 is required for its binding to DHX30. We show that the N-terminal 152 amino-acid residue segment of DHX30, denoted DHX30N, possesses all the antiviral activity of DHX30 and contains a dsRNA-binding domain, and that the NS1-DHX30 interaction in vivo requires the dsRNA-binding activity of both DHX30N and the NS1 RBD. We demonstrate why this is the case using bacteria-expressed proteins: the DHX30N-NS1 RBD interaction in vitro requires the presence of a dsRNA platform that binds both NS1 RBD and DHX30N. We propose that a similar dsRNA platform functions in interactions of the NS1 protein with other proteins that requires these same two amino-acid residues required for NS1 RBD dsRNA-binding activity.


mBio ◽  
2017 ◽  
Vol 8 (3) ◽  
Author(s):  
Shu-Ming Kuo ◽  
Chi-Jene Chen ◽  
Shih-Cheng Chang ◽  
Tzu-Jou Liu ◽  
Yi-Hsiang Chen ◽  
...  

ABSTRACT Avian influenza A viruses generally do not replicate efficiently in human cells, but substitution of glutamic acid (Glu, E) for lysine (Lys, K) at residue 627 of avian influenza virus polymerase basic protein 2 (PB2) can serve to overcome host restriction and facilitate human infectivity. Although PB2 residue 627 is regarded as a species-specific signature of influenza A viruses, host restriction factors associated with PB2627E have yet to be fully investigated. We conducted immunoprecipitation, followed by differential proteomic analysis, to identify proteins associating with PB2627K (human signature) and PB2627E (avian signature) of influenza A/WSN/1933(H1N1) virus, and the results indicated that Tu elongation factor, mitochondrial (TUFM), had a higher binding affinity for PB2627E than PB2627K in transfected human cells. Stronger binding of TUFM to avian-signature PB2590G/591Q and PB2627E in the 2009 swine-origin pandemic H1N1 and 2013 avian-origin H7N9 influenza A viruses was similarly observed. Viruses carrying avian-signature PB2627E demonstrated increased replication in TUFM-deficient cells, but viral replication decreased in cells overexpressing TUFM. Interestingly, the presence of TUFM specifically inhibited the replication of PB2627E viruses, but not PB2627K viruses. In addition, enhanced levels of interaction between TUFM and PB2627E were noted in the mitochondrial fraction of infected cells. Furthermore, TUFM-dependent autophagy was reduced in TUFM-deficient cells infected with PB2627E virus; however, autophagy remained consistent in PB2627K virus-infected cells. The results suggest that TUFM acts as a host restriction factor that impedes avian-signature influenza A virus replication in human cells in a manner that correlates with autophagy. IMPORTANCE An understanding of the mechanisms that influenza A viruses utilize to shift host tropism and the identification of host restriction factors that can limit infection are both critical to the prevention and control of emerging viruses that cross species barriers to target new hosts. Using a proteomic approach, we revealed a novel role for TUFM as a host restriction factor that exerts an inhibitory effect on avian-signature PB2627E influenza virus propagation in human cells. We further found that increased TUFM-dependent autophagy correlates with the inhibitory effect on avian-signature influenza virus replication and may serve as a key intrinsic mechanism to restrict avian influenza virus infection in humans. These findings provide new insight regarding the TUFM mitochondrial protein and may have important implications for the development of novel antiviral strategies. IMPORTANCE An understanding of the mechanisms that influenza A viruses utilize to shift host tropism and the identification of host restriction factors that can limit infection are both critical to the prevention and control of emerging viruses that cross species barriers to target new hosts. Using a proteomic approach, we revealed a novel role for TUFM as a host restriction factor that exerts an inhibitory effect on avian-signature PB2627E influenza virus propagation in human cells. We further found that increased TUFM-dependent autophagy correlates with the inhibitory effect on avian-signature influenza virus replication and may serve as a key intrinsic mechanism to restrict avian influenza virus infection in humans. These findings provide new insight regarding the TUFM mitochondrial protein and may have important implications for the development of novel antiviral strategies.


Oncogene ◽  
2018 ◽  
Vol 37 (48) ◽  
pp. 6275-6284 ◽  
Author(s):  
Elena Wüstenhagen ◽  
Fatima Boukhallouk ◽  
Inka Negwer ◽  
Krishnaraj Rajalingam ◽  
Frank Stubenrauch ◽  
...  

2016 ◽  
Vol 90 (18) ◽  
pp. 8085-8089 ◽  
Author(s):  
Ben Murrell ◽  
Thomas Vollbrecht ◽  
John Guatelli ◽  
Joel O. Wertheim

ABSTRACTMolecular evolutionary arms races between viruses and their hosts are important drivers of adaptation. These Red Queen dynamics have been frequently observed in primate retroviruses and their antagonists, host restriction factor genes, such as APOBEC3F/G, TRIM5-α, SAMHD1, and BST-2. Host restriction factors have experienced some of the most intense and pervasive adaptive evolution documented in primates. Recently, two novel host factors, SERINC3 and SERINC5, were identified as the targets of HIV-1 Nef, a protein crucial for the optimal infectivity of virus particles. Here, we compared the evolutionary fingerprints of SERINC3 and SERINC5 to those of other primate restriction factors and to a set of other genes with diverse functions. SERINC genes evolved in a manner distinct from the canonical arms race dynamics seen in the other restriction factors. Despite their antiviral activity against HIV-1 and other retroviruses, SERINC3 and SERINC5 have a relatively uneventful evolutionary history in primates.IMPORTANCERestriction factors are host proteins that block viral infection and replication. Many viruses, like HIV-1 and related retroviruses, evolved accessory proteins to counteract these restriction factors. The importance of these interactions is evidenced by the intense adaptive selection pressures that dominate the evolutionary histories of both the host and viral genes involved in this so-called arms race. The dynamics of these arms races can point to mechanisms by which these viral infections can be prevented. Two human genes, SERINC3 and SERINC5, were recently identified as targets of an HIV-1 accessory protein important for viral infectivity. Unexpectedly, we found that these SERINC genes, unlike other host restriction factor genes, show no evidence of a recent evolutionary arms race with viral pathogens.


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