Human Immunodeficiency Virus Type 1 Nef Inhibits Autophagy through Transcription Factor EB Sequestration

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Under basal conditions, the mammalian target of rapamycin (MTOR) phosphorylates transcription factor EB (TFEB) resulting in its cytoplasmic retention. When MTOR is inhibited, TFEB is dephosphorylated and translocated to the nucleus where it increases autophagy and lysosomal gene expression. As human immunodeficiency virus type 1 (HIV) Nef acts as an anti-autophagic maturation factor through interaction with beclin-1 (BECN1), we investigated the role of Nef and TFEB in the modulation of autophagy during HIV infection of human macrophages. We found that upon exposure to HIV, macrophages elicited an autophagic response through a toll-like receptor 8 (TLR8) and BECN1 dependent dephosphorylation and nuclear translocation of TFEB. However, once HIV infection is established, phosphorylation and cytoplasmic sequestration of TFEB as well as autophagy revert to pre-infection levels. Moreover, this reversion is dependent upon the presence of HIV Nef. Collectively, the data suggests that the interaction between HIV and TLR8 serves as a signal for autophagy induction that is dependent upon the dephosphorylation and nuclear translocation of TFEB. Once HIV establishes a productive infection, Nef binds BECN1 resulting in MTOR activation, TFEB phosphorylation and cytosolic sequestration and the inhibition of autophagy.

Vyšlo v časopise: Human Immunodeficiency Virus Type 1 Nef Inhibits Autophagy through Transcription Factor EB Sequestration. PLoS Pathog 11(6): e32767. doi:10.1371/journal.ppat.1005018
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1005018

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