SLC38A9 is directly involved in Tat-induced endolysosome dysfunction and senescence in astrocytes

Abstract

Cellular senescence contributes to accelerated aging and the development of various neurodegeneration disorders including HIV-associated neurocognitive disorders. The development of HIV-associated neurocognitive disorders is attributed, at least in part, to the CNS persistence of HIV-1 transactivator of transcription (Tat), an essential protein for viral transcription that is actively secreted from HIV-1-infected cells. Secreted Tat enters cells via receptor-mediated endocytosis and induces endolysosome dysfunction and cellular senescence in CNS cells. Given that endolysosome dysfunction represents an early step in exogenous Tat-induced cellular senescence, we tested the hypothesis that Tat induces cellular senescence via an endolysosome-dependent mechanism in human astrocytes. We demonstrated that internalized Tat interacts with an endolysosome-resident arginine sensor SLC38A9 via the arginine-rich basic domain. Such an interaction between Tat and SLC38A9 leads to endolysosome dysfunction, enhanced HIV-1 LTR transactivation, and cellular senescence. These findings suggest that endolysosome dysfunction drives the development of senescence and highlight the novel role of SLC38A9 in Tat-induced endolysosome dysfunction and astrocyte senescence.