Abstract
There is a significantly higher risk for type II diabetes in HIV-1 carriers, albeit the molecular mechanism for this HIV-related pathology remains enigmatic. The 52 amino acid HIV-1 p6 Gag protein is synthesized as the C-terminal part of the Gag polyprotein Pr55. In this context, p6 promotes virus release by its two late (L-) domains, and facilitates the incorporation of the viral accessory protein Vpr. However, the function of p6 in its mature form, after proteolytic release from Gag, has not been investigated yet. We found that the mature p6 represents the first known viral substrate of the ubiquitously expressed cytosolic metalloendopeptidase insulin-degrading enzyme (IDE). IDE is sufficient and required for degradation of p6, and p6 is approximately 100-fold more efficiently degraded by IDE than its eponymous substrate insulin. This observation appears to be specific for HIV-1, as p6 proteins from HIV-2 and simian immunodeficiency virus, as well as the 51 amino acid p9 from equine infectious anaemia virus were insensitive to IDE degradation. The amount of virus-associated p6, as well as the efficiency of release and maturation of progeny viruses does not depend on the presence of IDE in the host cells, as it was shown by CRISPR/Cas9 edited IDE KO cells. However, HIV-1 mutants harboring IDE-insensitive p6 variants exhibit reduced virus replication capacity, a phenomenon that seems to depend on the presence of an X4-tropic Env. Furthermore, competing for IDE by exogenous insulin or inhibiting IDE by the highly specific inhibitor 6bK, also reduced virus replication. This effect could be specifically attributed to IDE since replication of HIV-1 variants coding for an IDE-insensitive p6 were inert towards IDE-inhibition. Our cumulative data support a model in which removal of p6 during viral entry is important for virus replication, at least in the case of X4 tropic HIV-1.
Highlights
The 52 aa HIV-1 p6 protein is one of the smallest known lentiviral proteins
All functions of p6 have been attributed to those of its parental precursor protein, the Gag polyprotein Pr55, and almost nothing is known about the role of mature p6 in the HIV-1
All functions of p6 have been described in the context of p6 as the C-terminal part of the Gag polyprotein
Summary
The 52 aa HIV-1 p6 protein is one of the smallest known lentiviral proteins It is synthesized as the C-terminal part of the Gag polyprotein Pr55 and is released by viral protease (PR) during virus morphogenesis. It is abundantly present in progeny virions and after virus disintegration should be present in less characterized intra- and extracellular compartments, where its abundance and function have not been defined yet. Many functions have been ascribed to the C-terminal p6 region of Gag during late steps of virus replication, involving assembly, release, and maturation of progeny virions. Neither virus release and maturation, nor the amounts of particle-associated Vpr and p6 itself were altered in IDE knock out cells. Our cumulative data support a model in which IDE is responsible for the rapid degradation of p6 entering the cell as part of the incoming virion, a process that appears to be crucial to achieve optimal X4-tropic virus replication
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