RT Journal Article
SR Electronic
T1 SLC38A9 is directly involved in Tat-induced endolysosome dysfunction and senescence in astrocytes
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202503231
DO 10.26508/lsa.202503231
VO 8
IS 7
A1 Rezagholizadeh, Neda
A1 Datta, Gaurav
A1 Hasler, Wendie A
A1 Nguon, Erica C
A1 Smokey, Elise V
A1 Khan, Nabab
A1 Chen, Xuesong
YR 2025
UL http://www.life-science-alliance.org/content/8/7/e202503231.abstract
AB 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.Datasets reported in this study are not composed of standardized data types. No original code was reported in the study. All data generated or analyzed during this study are included in this published article and its supplementary information files. Any additional information required to reanalyze the data reported in this study is available from the lead contact upon request.