title: Human Immunodeficiency Virus Type 1 Nef Inhibits Autophagy through Transcription Factor EB Sequestration.
abstract: HIV Nef acts as an anti-autophagic maturation factor through interaction with beclin-1 (BECN1). We report that exposure of macrophages to infectious or non-infectious purified HIV induces toll-like receptor 8 (TLR8) and BECN1 dependent dephosphorylation and nuclear translocation of TFEB and that this correlates with an increase in autophagy markers. RNA interference for ATG13, TFEB, TLR8, or BECN1 inhibits this HIV-induced autophagy. However, once HIV establishes a productive infection, TFEB phosphorylation and cytoplasmic sequestration are increased resulting in decreased autophagy markers. Moreover, by 7 d post-infection, autophagy levels are similar to mock infected controls. Conversely, although Nef deleted HIV similarly induces TFEB dephosphorylation and nuclear localization, and increases autophagy, these levels remain elevated during continued productive infection. Thus, the interaction between HIV and TLR8 serves as a signal for autophagy induction that is dependent upon the dephosphorylation and nuclear translocation of TFEB. During permissive infection, Nef binds BECN1 resulting in mammalian target of rapamycin (MTOR) activation, TFEB phosphorylation and cytosolic sequestration, and the inhibition of autophagy. To our knowledge, this is the first report of a virus modulating TFEB localization and helps to explain how HIV modulates autophagy to promote its own replication and cell survival.
authors.affiliation: Division of Infectious Diseases, Department of Pediatrics, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Grant R
authors.initials: GR
authors.lastname: Campbell
authors.affiliation: Division of Infectious Diseases, Department of Pediatrics, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Pratima
authors.initials: P
authors.lastname: Rawat
authors.affiliation: Division of Infectious Diseases, Department of Pediatrics, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Rachel S
authors.initials: RS
authors.lastname: Bruckman
authors.affiliation: Division of Infectious Diseases, Department of Pediatrics, University of California San Diego, La Jolla, California, United States of America; Rady Children's Hospital, San Diego, California, United States of America.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Spector
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000276:immunology*; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism*; D000071186:Beclin-1; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D051200:Toll-Like Receptor 8 / Q000378:metabolism; D014779:Virus Replication / Q000276:immunology; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000276:immunology*
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D000071186:Beclin-1; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; C064972:TFEB protein, human; C495349:TLR8 protein, human; D051200:Toll-Like Receptor 8; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases