Interacting partners of macrophage-secreted cathepsin B contribute to HIV-induced neuronal apoptosis.

TitleInteracting partners of macrophage-secreted cathepsin B contribute to HIV-induced neuronal apoptosis.
Publication TypeJournal Article
Year of Publication2015
AuthorsCantres-Rosario, YM, Hernandez, N, Negron, K, Perez-Laspiur, J, Leszyk, J, Shaffer, SA, Meléndez, LM
JournalAIDS
Volume29
Issue16
Pagination2081-92
Date Published2015 Oct 23
ISSN1473-5571
KeywordsApoptosis, Cathepsin B, Cells, Cultured, Culture Media, Conditioned, External, Female, HIV Infections, HIV-1, Humans, Macrophages, Neurons
Abstract

OBJECTIVE: HIV-1 infection of macrophages increases cathepsin B secretion and induces neuronal apoptosis, but the molecular mechanism remains unclear.DESIGN: We identified macrophage-secreted cathepsin B protein interactions extracellularly and their contribution to neuronal death in vitro.METHODS: Cathepsin B was immunoprecipitated from monocyte-derived macrophage supernatants after 12 days postinfection. The cathepsin B interactome was identified by label-free tandem mass spectrometry and compared with uninfected supernatants. Proteins identified were validated by western blot. Neurons were exposed to macrophage-conditioned media in presence or absence of antibodies against cathepsin B and interacting proteins. Apoptosis was measured using TUNEL labeling. Immunohistochemistry of postmortem brain tissue samples from healthy, HIV-infected and Alzheimer's disease patients was performed to observe the ex-vivo expression of the proteins identified.RESULTS: Nine proteins co-immunoprecipitated differentially with cathepsin B between uninfected and HIV-infected macrophages. Serum amyloid P component (SAPC)-cathepsin B interaction increased in HIV-infected macrophage supernatants, while matrix metalloprotease 9 (MMP-9)-cathepsin B interaction decreased. Pre-treatment of HIV-infected macrophage-conditioned media with antibodies against cathepsin B and SAPC decreased neuronal apoptosis. The addition of MMP-9 antibodies was not neuro-protective SAPC was overexpressed in postmortem brain tissue from HIV-positive neurocognitive impaired patients compared with HIV positive with normal cognition and healthy controls, although MMP-9 expression was similar in all tissues.CONCLUSION: Inhibiting SAPC-cathepsin B interaction protects against HIV-induced neuronal death and may help to find alternative treatments for HIV-associated neurocognitive disorders.

DOI10.1097/QAD.0000000000000823
Alternate JournalAIDS
PubMed ID26208400
PubMed Central IDPMC4636939
Grant ListU01 MH083507 / MH / NIMH NIH HHS / United States
R24 MH059724 / MH / NIMH NIH HHS / United States
U01 MH083500 / MH / NIMH NIH HHS / United States
8G12MD007600 / MD / NIMHD NIH HHS / United States
R01MH083516 / MH / NIMH NIH HHS / United States
R24 NS045491 / NS / NINDS NIH HHS / United States
N01MH32002 / MH / NIMH NIH HHS / United States
R25 GM061838 / GM / NIGMS NIH HHS / United States
U24 MH100928 / MH / NIMH NIH HHS / United States
5U01MH083500 / MH / NIMH NIH HHS / United States
R24MH59724 / MH / NIMH NIH HHS / United States
R24 MH059745 / MH / NIMH NIH HHS / United States
R24MH59745 / MH / NIMH NIH HHS / United States
U54 NS043011 / NS / NINDS NIH HHS / United States
U54NS043011 / NS / NINDS NIH HHS / United States
P20RR016470-12 / RR / NCRR NIH HHS / United States
R24 NS038841 / NS / NINDS NIH HHS / United States
P20 RR016470 / RR / NCRR NIH HHS / United States
R24 NS45491 / NS / NINDS NIH HHS / United States
NS 38841 / NS / NINDS NIH HHS / United States
R25GM061838 / GM / NIGMS NIH HHS / United States
G12 RR003051 / RR / NCRR NIH HHS / United States
U01MH083501 / MH / NIMH NIH HHS / United States
U01 MH083501 / MH / NIMH NIH HHS / United States
SC1 GM113691 / GM / NIGMS NIH HHS / United States
U01MH083506 / MH / NIMH NIH HHS / United States
U01 MH083545 / MH / NIMH NIH HHS / United States
U01 MH083506 / MH / NIMH NIH HHS / United States
R01 MH083516 / MH / NIMH NIH HHS / United States
U01MH083507 / MH / NIMH NIH HHS / United States
G12 MD007600 / MD / NIMHD NIH HHS / United States
U01MH083545 / MH / NIMH NIH HHS / United States