KSHV reduces autophagy in THP-1 cells and in differentiating monocytes by decreasing CAST/calpastatin and ATG5 expression

Santarelli, Roberta; Granato, Marisa; Pentassuglia, G.; Lacconi, Valentina; Montani, Maria Saveria Gilardini; Gonnella, Roberta; Tafani, Marco; Torrisi, Maria Rosaria; Faggioni, Alberto; Cirone, Mara

doi:10.1080/15548627.2016.1235122

Cited by 32 publications

(33 citation statements)

References 101 publications

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“…It has been reported that autophagy, induced by CSF2/ GM-CSF (colony stimulating factor 2), is essential for proper monocyte in vitro differentiation into DCs [15]. Consistent with these results, we have recently shown that KSHV, as well as other completely unrelated oncoviruses such as hepatitis C virus (HCV), reduced autophagy to impair DC formation [12,16,17], although through different strategies.…”

Section: Introductionsupporting

confidence: 84%

“…Autophagy, induced by CSF2 has been reported to be essential for monocyte differentiation into DCs [15]. Since EBV interferes with the autophagic process in other cell types [37] and autophagy inhibition by other oncoviruses results in an impairment of the differentiation process in infected monocytes [12,17], we investigated whether the reduction of DC formation mediated by EBV could correlate with autophagy inhibition. As shown in Figure 3(a), the expression level of the autophagic marker MAP1LC3-II/LC3-II (microtubule associated protein 1 light chain 3)-II was reduced in the presence of bafilomycin A 1 (BAF) [38] in a time-dependent fashion in EBV-infected monocytes compared to the mock control cells, indicating that the autophagic flux was reduced by EBVinfection.…”

Section: Ebv Reduces Autophagy In Differentiating Monocytesmentioning

confidence: 99%

“…It belongs to gammaherpesvirus family, together with Kaposi sarcoma-associated herpesvirus (KSHV), that is also linked to the pathogenesis of several human malignancies [3,4]. Besides having protumorigenic effects, both viruses interfere with the immune system cell function [5,6] and in particular of dendritic cells (DCs) [7][8][9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

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EBV reduces autophagy, intracellular ROS and mitochondria to impair monocyte survival and differentiation

et al. 2018

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EBV has been reported to impair monocyte in vitro differentiation into dendritic cells (DCs) and reduce cell survival. In this study, we added another layer of knowledge to this topic and showed that these effects correlated with macroautophagy/autophagy, ROS and mitochondrial biogenesis reduction. Of note, autophagy and ROS, although strongly interconnected, have been separately reported to be induced by CSF2/GM-CSF (colony stimulating factor 2) and required for CSF2-IL4-driven monocyte in vitro differentiation into DCs. We show that EBV infects monocytes and initiates a feedback loop in which, by inhibiting autophagy, reduces ROS and through ROS reduction negatively influences autophagy. Mechanistically, autophagy reduction correlated with the downregulation of RAB7 and ATG5 expression and STAT3 activation, leading to the accumulation of SQSTM1/p62. The latter activated the SQSTM1-KEAP1-NFE2L2 axis and upregulated the anti-oxidant response, reducing ROS and further inhibiting autophagy. ROS decrease correlated also with the reduction of mitochondria, the main source of intracellular ROS, achieved by the downregulation of NRF1 and TFAM, mitochondrial biogenesis transcription factors. Interestingly, mitochondria supply membranes and ATP required for autophagy execution, thus their reduction may further reduce autophagy in EBV-infected monocytes. In conclusion, this study shows for the first time that the interconnected reduction of autophagy, intracellular ROS and mitochondria mediated by EBV switches monocyte differentiation into apoptosis, giving new insights into the mechanisms through which this virus reduces immune surveillance.

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Section: Introductionsupporting

confidence: 84%

Section: Ebv Reduces Autophagy In Differentiating Monocytesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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EBV reduces autophagy, intracellular ROS and mitochondria to impair monocyte survival and differentiation

et al. 2018

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“…Moreover, it has been reported that JNK activation stimulates the autophagy by interfering with Bcl-2/Beclin interaction and that the pharmacological inhibition of JNK causes accumulation of p62 and reduces the LC3II/LC3I ratio flux and activates caspase 3. In particular, p54 JNK phosphorylation may support cell survival during cellular stress, while viral infections such as Kaposi sarcoma-associated herpes virus infections are able to inhibit p54 JNK phosphorylation, thus inhibiting autophagy and reducing cell survival [67–69]. In agreement with these results, the inhibition of p54 JNK phosphorylation by CUR further supports the block of the autophagic flux and the induction of apoptosis in MM cells.…”

Section: Discussionsupporting

confidence: 54%

Curcumin blocks autophagy and activates apoptosis of malignant mesothelioma cell lines and increases the survival of mice intraperitoneally transplanted with a malignant mesothelioma cell line

et al. 2017

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Malignant mesothelioma (MM) is a primary tumor arising from the serous membranes. The resistance of MM patients to conventional therapies, and the poor patients’ survival, encouraged the identification of molecular targets for MM treatment. Curcumin (CUR) is a “multifunctional drug”. We explored the in vitro effects of CUR on cell proliferation, cell cycle regulation, pro-survival signaling pathways, apoptosis, autophagy of human (MM-B1, H-Meso-1, MM-F1), and mouse (#40a) MM cells. In addition, we evaluated the in vivo anti-tumor activities of CUR in C57BL/6 mice intraperitoneally transplanted with #40a cells forming ascites.CUR in vitro inhibited MM cells survival in a dose- and time-dependent manner and increased reactive oxygen species’intracellular production and induced DNA damage. CUR triggered autophagic flux, but the process was then blocked and was coincident with caspase 8 activation which activates apoptosis. CUR-mediated apoptosis was supported by the increase of Bax/Bcl-2 ratio, increase of p53 expression, activation of caspase 9, cleavage of PARP-1, increase of the percentage of cells in the sub G1 phase which was reduced (MM-F1 and #40a) or abolished (MM-B1 and H-Meso-1) after MM cells incubation with the apoptosis inhibitor Z-VAD-FMK. CUR treatment stimulated the phosphorylation of ERK1/2 and p38 MAPK, inhibited that of p54 JNK and AKT, increased c-Jun expression and phosphorylation and prevented NF-κB nuclear translocation. Intraperitoneal administration of CUR increased the median survival of C57BL/6 mice intraperitoneally transplanted with #40a cells and reduced the risk of developing tumors. Our findings may have important implications for the design of MM treatment using CUR.

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“…Monocytes were isolated from human PBMCs of healthy donors as previously described and infected with 293‐EBV supernatants from 293/EBV cells containing recombinant B95‐8 virus obtained as previously described . In some experiments, B lymphocytes isolated from human peripheral blood mononuclear cells by using anti‐CD19 monoclonal antibody‐conjugated magnetic microbeads (130‐050‐301; Miltenyi Biotec, Bergisch Gladbach, Germany) were exposed to EBV as above reported for monocytes.…”

Section: Methodsmentioning

confidence: 99%

EBV up-regulates PD-L1 on the surface of primary monocytes by increasing ROS and activating TLR signaling and STAT3

Montani

Santarelli

Falcinelli

et al. 2018

Journal of Leukocyte Biology

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Programmed death ligand 1 (PD-L1) (also called B7-H1) is a membrane immune-modulatory protein whose overexpression on the surface of tumor cells as well as APCs impairs T-cell-mediated killing. Viruses that establish chronic infections have developed a number of strategies to escape from immune recognition including the up-regulation of PD-L1. This study shows for the first time that the human oncovirus EBV infects human primary monocytes using HLA-DR and induced a strong up-regulation of PD-L1 expression on their surface. Searching for the underlying mechanism/s leading to this immune suppressive effect, we found that EBV activated TLR signaling, increased intracellular ROS, and phosphorylated STAT3. Targeting these molecules partially reverted PD-L1 up-regulation that correlated with an altered cytokine production and a reduction of monocyte cell survival, strongly impairing the antiviral immune response.

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KSHV reduces autophagy in THP-1 cells and in differentiating monocytes by decreasing CAST/calpastatin and ATG5 expression

Cited by 32 publications

References 101 publications

EBV reduces autophagy, intracellular ROS and mitochondria to impair monocyte survival and differentiation

EBV reduces autophagy, intracellular ROS and mitochondria to impair monocyte survival and differentiation

Curcumin blocks autophagy and activates apoptosis of malignant mesothelioma cell lines and increases the survival of mice intraperitoneally transplanted with a malignant mesothelioma cell line

EBV up-regulates PD-L1 on the surface of primary monocytes by increasing ROS and activating TLR signaling and STAT3

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