Proteolysis of mature HIV-1 p6 Gag protein by the insulin-degrading enzyme (IDE) regulates virus replication in an Env-dependent manner

Autor: Hahn, Friedrich, Schmalen, Adrian, Setz, Christian, Friedrich, Melanie, Schlößer, Stefan, Kölle, Julia, Spranger, Robert, Rauch, Pia, Fraedrich, Kirsten, Reif, Tatjana, Karius-Fischer, Julia, Balasubramanyam, Ashok, Henklein, Petra, Fossen, Torgils, Schubert, Ulrich
Jazyk: angličtina
Rok vydání: 2017
Předmět:
RNA viruses
Molecular biology
T-Lymphocytes
viruses
lcsh:Medicine
Virus Replication
Pathology and Laboratory Medicine
Insulysin
gag Gene Products
Human Immunodeficiency Virus
Biochemistry
Virions
Database and Informatics Methods
Endocrinology
Immunodeficiency Viruses
Medizinische Fakultät
Medicine and Health Sciences
Insulin
lcsh:Science
Cells
Cultured
SIV
Medical Microbiology
Viral Pathogens
Viruses
Pathogens
Sequence Analysis
Research Article
Bioinformatics
Viral Structure
DNA construction
Research and Analysis Methods
Microbiology
Sequence Motif Analysis
Virology
Retroviruses
Humans
ddc:610
Microbial Pathogens
Diabetic Endocrinology
Lentivirus
lcsh:R
Organisms
Gene Products
env
Biology and Life Sciences
HIV
Hormones
Viral Replication
Molecular biology techniques
Proteolysis
HIV-2
Plasmid Construction
HIV-1
lcsh:Q
HeLa Cells
Zdroj: PLoS ONE, Vol 12, Iss 4, p e0174254 (2017)
PLoS ONE
ISSN: 1932-6203
Popis: 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.
Databáze: OpenAIRE
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