The N-Terminus of the HIV-1 p6 Gag Protein Regulates Susceptibility to Degradation by IDE
As part of the Pr55<sup>Gag</sup> polyprotein, p6 fulfills an essential role in the late steps of the replication cycle. However, almost nothing is known about the functions of the mature HIV-1 p6 protein. Recently, we showed that p6 is a bona fide substrate of the insulin-degrading enzy...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2018-12-01
|
| Series: | Viruses |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1999-4915/10/12/710 |
| _version_ | 1818021925968936960 |
|---|---|
| author | Adrian Schmalen Julia Karius-Fischer Pia Rauch Christian Setz Klaus Korn Petra Henklein Torgils Fossen Ulrich Schubert |
| author_facet | Adrian Schmalen Julia Karius-Fischer Pia Rauch Christian Setz Klaus Korn Petra Henklein Torgils Fossen Ulrich Schubert |
| author_sort | Adrian Schmalen |
| collection | DOAJ |
| description | As part of the Pr55<sup>Gag</sup> polyprotein, p6 fulfills an essential role in the late steps of the replication cycle. However, almost nothing is known about the functions of the mature HIV-1 p6 protein. Recently, we showed that p6 is a bona fide substrate of the insulin-degrading enzyme (IDE), a ubiquitously expressed zinc metalloprotease. This phenomenon appears to be specific for HIV-1, since p6 homologs of HIV-2, SIV and EIAV were IDE-insensitive. Furthermore, abrogation of the IDE-mediated degradation of p6 reduces the replication capacity of HIV-1 in an Env-dependent manner. However, it remained unclear to which extent the IDE mediated degradation is phylogenetically conserved among HIV-1. Here, we describe two HIV-1 isolates with IDE resistant p6 proteins. Sequence comparison allowed deducing one single amino acid regulating IDE sensitivity of p6. Exchanging the N-terminal leucine residue of p6 derived from the IDE sensitive isolate HIV-1<sub>NL4-3</sub> with proline enhances its stability, while replacing Pro-1 of p6 from the IDE insensitive isolate SG3 with leucine restores susceptibility towards IDE. Phylogenetic analyses of this natural polymorphism revealed that the N-terminal leucine is characteristic for p6 derived from HIV-1 group M except for subtype A, which predominantly expresses p6 with an N-terminal proline. Consequently, p6 peptides derived from subtype A are not degraded by IDE. Thus, IDE mediated degradation of p6 is specific for HIV-1 group M isolates and not occasionally distributed among HIV-1. |
| first_indexed | 2024-04-14T08:25:42Z |
| format | Article |
| id | doaj.art-e91b4b96925e4478a6f09e72f46365f7 |
| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-04-14T08:25:42Z |
| publishDate | 2018-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj.art-e91b4b96925e4478a6f09e72f46365f72022-12-22T02:04:05ZengMDPI AGViruses1999-49152018-12-01101271010.3390/v10120710v10120710The N-Terminus of the HIV-1 p6 Gag Protein Regulates Susceptibility to Degradation by IDEAdrian Schmalen0Julia Karius-Fischer1Pia Rauch2Christian Setz3Klaus Korn4Petra Henklein5Torgils Fossen6Ulrich Schubert7Institute of Virology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), 91054 Erlangen, GermanyInstitute of Virology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), 91054 Erlangen, GermanyInstitute of Virology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), 91054 Erlangen, GermanyInstitute of Virology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), 91054 Erlangen, GermanyInstitute of Virology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), 91054 Erlangen, GermanyInstitute of Biochemistry, Charité—Universitätsmedizin Berlin, 10117 Berlin, GermanyDepartment of Chemistry, University of Bergen, 5020 Bergen, NorwayInstitute of Virology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), 91054 Erlangen, GermanyAs part of the Pr55<sup>Gag</sup> polyprotein, p6 fulfills an essential role in the late steps of the replication cycle. However, almost nothing is known about the functions of the mature HIV-1 p6 protein. Recently, we showed that p6 is a bona fide substrate of the insulin-degrading enzyme (IDE), a ubiquitously expressed zinc metalloprotease. This phenomenon appears to be specific for HIV-1, since p6 homologs of HIV-2, SIV and EIAV were IDE-insensitive. Furthermore, abrogation of the IDE-mediated degradation of p6 reduces the replication capacity of HIV-1 in an Env-dependent manner. However, it remained unclear to which extent the IDE mediated degradation is phylogenetically conserved among HIV-1. Here, we describe two HIV-1 isolates with IDE resistant p6 proteins. Sequence comparison allowed deducing one single amino acid regulating IDE sensitivity of p6. Exchanging the N-terminal leucine residue of p6 derived from the IDE sensitive isolate HIV-1<sub>NL4-3</sub> with proline enhances its stability, while replacing Pro-1 of p6 from the IDE insensitive isolate SG3 with leucine restores susceptibility towards IDE. Phylogenetic analyses of this natural polymorphism revealed that the N-terminal leucine is characteristic for p6 derived from HIV-1 group M except for subtype A, which predominantly expresses p6 with an N-terminal proline. Consequently, p6 peptides derived from subtype A are not degraded by IDE. Thus, IDE mediated degradation of p6 is specific for HIV-1 group M isolates and not occasionally distributed among HIV-1.https://www.mdpi.com/1999-4915/10/12/710HIV-1p6insulin-degrading enzymeL1PL449Pcleavage-sitedegradationproteolysisstabilitysubtypes |
| spellingShingle | Adrian Schmalen Julia Karius-Fischer Pia Rauch Christian Setz Klaus Korn Petra Henklein Torgils Fossen Ulrich Schubert The N-Terminus of the HIV-1 p6 Gag Protein Regulates Susceptibility to Degradation by IDE Viruses HIV-1 p6 insulin-degrading enzyme L1P L449P cleavage-site degradation proteolysis stability subtypes |
| title | The N-Terminus of the HIV-1 p6 Gag Protein Regulates Susceptibility to Degradation by IDE |
| title_full | The N-Terminus of the HIV-1 p6 Gag Protein Regulates Susceptibility to Degradation by IDE |
| title_fullStr | The N-Terminus of the HIV-1 p6 Gag Protein Regulates Susceptibility to Degradation by IDE |
| title_full_unstemmed | The N-Terminus of the HIV-1 p6 Gag Protein Regulates Susceptibility to Degradation by IDE |
| title_short | The N-Terminus of the HIV-1 p6 Gag Protein Regulates Susceptibility to Degradation by IDE |
| title_sort | n terminus of the hiv 1 p6 gag protein regulates susceptibility to degradation by ide |
| topic | HIV-1 p6 insulin-degrading enzyme L1P L449P cleavage-site degradation proteolysis stability subtypes |
| url | https://www.mdpi.com/1999-4915/10/12/710 |
| work_keys_str_mv | AT adrianschmalen thenterminusofthehiv1p6gagproteinregulatessusceptibilitytodegradationbyide AT juliakariusfischer thenterminusofthehiv1p6gagproteinregulatessusceptibilitytodegradationbyide AT piarauch thenterminusofthehiv1p6gagproteinregulatessusceptibilitytodegradationbyide AT christiansetz thenterminusofthehiv1p6gagproteinregulatessusceptibilitytodegradationbyide AT klauskorn thenterminusofthehiv1p6gagproteinregulatessusceptibilitytodegradationbyide AT petrahenklein thenterminusofthehiv1p6gagproteinregulatessusceptibilitytodegradationbyide AT torgilsfossen thenterminusofthehiv1p6gagproteinregulatessusceptibilitytodegradationbyide AT ulrichschubert thenterminusofthehiv1p6gagproteinregulatessusceptibilitytodegradationbyide AT adrianschmalen nterminusofthehiv1p6gagproteinregulatessusceptibilitytodegradationbyide AT juliakariusfischer nterminusofthehiv1p6gagproteinregulatessusceptibilitytodegradationbyide AT piarauch nterminusofthehiv1p6gagproteinregulatessusceptibilitytodegradationbyide AT christiansetz nterminusofthehiv1p6gagproteinregulatessusceptibilitytodegradationbyide AT klauskorn nterminusofthehiv1p6gagproteinregulatessusceptibilitytodegradationbyide AT petrahenklein nterminusofthehiv1p6gagproteinregulatessusceptibilitytodegradationbyide AT torgilsfossen nterminusofthehiv1p6gagproteinregulatessusceptibilitytodegradationbyide AT ulrichschubert nterminusofthehiv1p6gagproteinregulatessusceptibilitytodegradationbyide |