Interacting partners of macrophage-secreted cathepsin B contribute to HIV-induced neuronal apoptosis.
Title | Interacting partners of macrophage-secreted cathepsin B contribute to HIV-induced neuronal apoptosis. |
Publication Type | Journal Article |
Year of Publication | 2015 |
Authors | Cantres-Rosario, YM, Hernandez, N, Negron, K, Perez-Laspiur, J, Leszyk, J, Shaffer, SA, Meléndez, LM |
Journal | AIDS |
Volume | 29 |
Issue | 16 |
Pagination | 2081-92 |
Date Published | 2015 Oct 23 |
ISSN | 1473-5571 |
Keywords | Apoptosis, 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. |
DOI | 10.1097/QAD.0000000000000823 |
Alternate Journal | AIDS |
PubMed ID | 26208400 |
PubMed Central ID | PMC4636939 |
Grant List | U01 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 P20 GM103475 / GM / NIGMS 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 |