title: Degradation of HIV-1 integrase by the N-end rule pathway.
abstract: Human immunodeficiency virus type-1 (HIV-1) integrase catalyzes the irreversible insertion of the viral genome into host chromosomal DNA. We have developed a mammalian expression system for the synthesis of authentic HIV-1 integrase in the absence of other viral proteins. Integrase, which bears a N-terminal phenylalanine, was found to be a short-lived protein in human embryo kidney 293T cells. The degradation of integrase could be suppressed by proteasome inhibitors. N-terminal phenylalanine is recognized as a degradation signal by a ubiquitin-proteasome proteolytic system known as the N-end rule pathway. The replacement of N-terminal phenylalanine with methionine, valine, or glycine, which are stabilizing residues in the N-end rule, resulted in metabolically stabilized integrase proteins (half-life of N-terminal Met-integrase was at least 3 h). Conversely, the substitution of N-terminal phenylalanine with other destabilizing residues retained the metabolic instability of integrase. These findings indicate that the HIV-1 integrase is a physiological substrate of the N-end rule. We discuss a possible functional similarity to the better understood turnover of the bacteriophage Mu transposase and functions of integrase instability to the maintenance and integrity of the host cell genome.
authors.affiliation: Aaron Diamond AIDS Research Center, The Rockefeller University, New York, New York 10016, USA.
authors.forename: L C
authors.initials: LC
authors.lastname: Mulder
authors.forename: M A
authors.initials: MA
authors.lastname: Muesing
mesh_terms: D019427:HIV Integrase / Q000378:metabolism*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D014779:Virus Replication
chemical_list: D019427:HIV Integrase