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The N-Terminus of the HIV-1 p6 Gag Protein Regulates Susceptibility to Degradation by IDE

1
Institute of Virology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
2
Institute of Biochemistry, Charité—Universitätsmedizin Berlin, 10117 Berlin, Germany
3
Department of Chemistry, University of Bergen, 5020 Bergen, Norway
*
Author to whom correspondence should be addressed.
Viruses 2018, 10(12), 710; https://doi.org/10.3390/v10120710
Received: 13 November 2018 / Revised: 7 December 2018 / Accepted: 9 December 2018 / Published: 12 December 2018
(This article belongs to the Section Animal Viruses)
As part of the Pr55Gag 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-1NL4-3 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. View Full-Text
Keywords: HIV-1; p6; insulin-degrading enzyme; L1P; L449P; cleavage-site; degradation; proteolysis; stability; subtypes HIV-1; p6; insulin-degrading enzyme; L1P; L449P; cleavage-site; degradation; proteolysis; stability; subtypes
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Schmalen, A.; Karius-Fischer, J.; Rauch, P.; Setz, C.; Korn, K.; Henklein, P.; Fossen, T.; Schubert, U. The N-Terminus of the HIV-1 p6 Gag Protein Regulates Susceptibility to Degradation by IDE. Viruses 2018, 10, 710.

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