HIV-1 Tat Promotes Lysosomal Exocytosis in Astrocytes and Contributes to Astrocyte-mediated Tat Neurotoxicity.
Tat interaction with astrocytes has been shown to be important for Tat neurotoxicity and HIV/neuroAIDS. We have recently shown that Tat expression leads to increased glial fibrillary acidic protein (GFAP) expression and aggregation and activation of unfolded protein response/endoplasmic reticulum (ER) stress in astrocytes and causes neurotoxicity. However, the exact molecular mechanism of astrocyte-mediated Tat neurotoxicity is not defined. In this study, we showed that neurotoxic factors other than Tat protein itself were present in the supernatant of Tat-expressing astrocytes. Two-dimensional gel electrophoresis and mass spectrometry revealed significantly elevated lysosomal hydrolytic enzymes and plasma membrane-associated proteins in the supernatant of Tat-expressing astrocytes. We confirmed that Tat expression and infection of pseudotyped HIV.GFP led to increased lysosomal exocytosis from mouse astrocytes and human astrocytes. We found that Tat-induced lysosomal exocytosis was tightly coupled to astrocyte-mediated Tat neurotoxicity. In addition, we demonstrated that Tat-induced lysosomal exocytosis was astrocyte-specific and required GFAP expression and was mediated by ER stress. Taken together, these results show for the first time that Tat promotes lysosomal exocytosis in astrocytes and causes neurotoxicity through GFAP activation and ER stress induction in astrocytes and suggest a common cascade through which aberrant astrocytosis/GFAP up-regulation potentiates neurotoxicity and contributes to neurodegenerative diseases.
From the Department of Cell Biology and Immunology, Graduate School of Biomedical Sciences, University of North Texas Health Science Center, Fort Worth, Texas 76107.
Yan
Y
Fan
From the Department of Cell Biology and Immunology, Graduate School of Biomedical Sciences, University of North Texas Health Science Center, Fort Worth, Texas 76107 johnny.he@unthsc.edu.
Johnny J
http://orcid.org/0000-0002-0837-4889
JJ
He
D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D059865:Endoplasmic Reticulum Stress; D005089:Exocytosis; D005904:Glial Fibrillary Acidic Protein / Q000096:biosynthesis / Q000235:genetics; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D020258:Neurotoxicity Syndromes / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*
D005904:Glial Fibrillary Acidic Protein; C528900:glial fibrillary astrocytic protein, mouse; D054322:tat Gene Products, Human Immunodeficiency Virus
astrocyte; cathepsin B (CTSB); exocytosis; glial cell; human immunodeficiency virus (HIV); neuron