Cathepsin B and cystatin B in HIV-seropositive women are associated with infection and HIV-1-associated neurocognitive disorders

Cantres-Rosario, Yisel M.; Plaud-Valentín, Marinés; Gerena, Yamil; Skolasky, Richard L.; Wojna, Valerie; Meléndez, Loyda M.

doi:10.1097/qad.0b013e32835b3e47

Cited by 28 publications

(41 citation statements)

References 57 publications

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“…Thus, it is important to maintain the homeostasis of those enzymes or lysosomal exocytosis. Consistent with our findings, increased cathepsin B release has recently been linked to HIV infectionassociated neuronal death and neurocognitive deficits (76,77). Taken together, these findings suggest important roles of lysosomal exocytosis and cathepsins in neurodegenerative diseases, including HIV/neuroAIDS, and may provide new strategies for development of therapeutics for those diseases.…”

Section: Discussionsupporting

confidence: 90%

HIV-1 Tat Promotes Lysosomal Exocytosis in Astrocytes and Contributes to Astrocyte-mediated Tat Neurotoxicity

Fan

2016

Journal of Biological Chemistry

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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 membraneassociated 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 Tatinduced lysosomal exocytosis was tightly coupled to astrocytemediated 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.

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Section: Discussionsupporting

confidence: 90%

HIV-1 Tat Promotes Lysosomal Exocytosis in Astrocytes and Contributes to Astrocyte-mediated Tat Neurotoxicity

Fan

2016

Journal of Biological Chemistry

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“…Plasma cathepsin B secretion and activity is increased in HIV-seropositive cocaine-users It has been reported that cathepsin B increases in plasma of HIV-seropositive women as compared to HIV seronegative controls (Cantres-Rosario et al 2013). We next asked if cocaine use affected cathepsin B is expression and activity.…”

Section: Resultsmentioning

confidence: 99%

“…Plasma and CSF samples were obtained from a repository of samples of the Hispanic Women cohort followed at the Specialized NeuroAIDS Research Program of the University of Puerto Rico Medical Sciences Campus from 2001-2009 (Wojna et al 2006; Cantres-Rosario et al 2013) following approval by the Institutional Human Subject Review Board (IRB #0720109, 0720102). Patient demographics were as follows: HIV-1 infected women with combined antiretroviral therapy (cART), ages 26-48 years, and nondrug users defined by a urine toxicology screen (n=6).…”

Section: Methodsmentioning

confidence: 99%

“…Recently, we reported that HIV-1 infection induces cathepsin B in plasma of HIV infected patients (Cantres-Rosario et al 2013) and that cathepsin B secreted from HIV-1 infected MDM contributes to neuronal apoptosis (Rodriguez-Franco et al 2012), but, the effects of cocaine in cathepsin B secretion were unknown. In this work, we hypothesized that cocaine potentiates the detrimental effects of HIV-1 in MDM and promotes an increase of cathepsin B secretion and neuronal apoptosis.…”

Section: Introductionmentioning

confidence: 99%

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Cocaine Potentiates Cathepsin B Secretion and Neuronal Apoptosis from HIV-Infected Macrophages

Zenón

Segarra

Gonzalez

et al. 2014

J Neuroimmune Pharmacol

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Substance abuse is a risk factor for HIV infection and progression to AIDS. Recent evidence establishes that cocaine use promotes brain perivascular macrophage infiltration and microglia activation. The lysosomal protease cathepsin B is increased in monocytes from patients with HIV dementia and its secretion induces 10-15% of neurotoxicity. Here we asked if cocaine potentiates cathepsin B secretion from HIV-infected monocyte-derived macrophages (MDM) and its effect in neuronal apoptosis. Samples of plasma, CSF, and post-mortem brain tissue from HIV positive patients that used cocaine were tested for cathepsin B and its inhibitors to determine the in vivo relevance of these findings. MDM were inoculated with HIV-1ADA, exposed to cocaine, and the levels of secreted and bioactive cathepsin B and its inhibitors were measured at different time-points. Cathepsin B expression (p<0.001) and activity (p<0.05) increased in supernatants from HIV-infected cocaine treated MDM compared with HIV-infected cocaine negative controls. Increased levels of cystatin B expression was also found in supernatants from HIV-cocaine treated MDM (p<0.05). A significant increase in 30% of apoptotic neurons was obtained that decreased to 5% with the specific cathepsin B inhibitor (CA-074) or with cathepsin B antibody. Cathepsin B was significantly increased in the plasma and post-mortem brain tissue of HIV/cocaine users over non-drug users. Our results demonstrated that cocaine potentiates cathepsin B secretion in HIV-infected MDM and increase neuronal apoptosis. These findings provide new evidence that cocaine synergize with HIV-1 infection in increasing cathepsin B secretion and neurotoxicity.

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“…Therefore, selected cystatins are now being used as biomarkers to determine the disease severity and to predict patient outcomes (7,8,(38)(39)(40)(41). Subsequently, the replenishment of selected cystatins has been shown to be a promising treatment, specifically in certain types of cancer, to regulate tissue-damaging inflammation and maintain the integrity of the endothelium to prevent tumor metastasis (2,7,9,37).…”

Section: Discussionmentioning

confidence: 99%

Immunomodulatory and Antibacterial Effects of Cystatin 9 against Francisella tularensis

Eaves-Pyles

Patel

Arigi

et al. 2013

Mol Med

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Cystatin 9 (CST9) is a member of the type 2 cysteine protease inhibitor family, which has been shown to have immunomodulatory effects that restrain inflammation, but its functions against bacterial infections are unknown. Here, we report that purified human recombinant (r)CST9 protects against the deadly bacterium Francisella tularensis (Ft) in vitro and in vivo. Macrophages infected with the Ft human pathogen Schu 4 (S4), then given 50 pg of rCST9 exhibited significantly decreased intracellular bacterial replication and increased killing via preventing the escape of S4 from the phagosome. Further, rCST9 induced autophagy in macrophages via the regulation of the mammalian target of rapamycin (mTOR) signaling pathways. rCST9 promoted the upregulation of macrophage proteins involved in antiinflammation and antiapoptosis, while restraining proinflammatory-associated proteins. Interestingly, the viability and virulence of S4 also was decreased directly by rCST9. In a mouse model of Ft inhalation, rCST9 significantly decreased organ bacterial burden and improved survival, which was not accompanied by excessive cytokine secretion or subsequent immune cell migration. The current report is the first to show the immunomodulatory and antimicrobial functions of rCST9 against Ft. We hypothesize that the attenuation of inflammation by rCST9 may be exploited for therapeutic purposes during infection.

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Cathepsin B and cystatin B in HIV-seropositive women are associated with infection and HIV-1-associated neurocognitive disorders

Cited by 28 publications

References 57 publications

HIV-1 Tat Promotes Lysosomal Exocytosis in Astrocytes and Contributes to Astrocyte-mediated Tat Neurotoxicity

HIV-1 Tat Promotes Lysosomal Exocytosis in Astrocytes and Contributes to Astrocyte-mediated Tat Neurotoxicity

Cocaine Potentiates Cathepsin B Secretion and Neuronal Apoptosis from HIV-Infected Macrophages

Immunomodulatory and Antibacterial Effects of Cystatin 9 against Francisella tularensis

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