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1.
Autophagy ; 14(1): 22-37, 2018.
Article in English | MEDLINE | ID: mdl-29130391

ABSTRACT

Vici syndrome is a human inherited multi-system disorder caused by recessive mutations in EPG5, encoding the EPG5 protein that mediates the fusion of autophagosomes with lysosomes. Immunodeficiency characterized by lack of memory B cells and increased susceptibility to infection is an integral part of the condition, but the role of EPG5 in the immune system remains unknown. Here we show that EPG5 is indispensable for the transport of the TLR9 ligand CpG to the late endosomal-lysosomal compartment, and for TLR9-initiated signaling, a step essential for the survival of human memory B cells and their ultimate differentiation into plasma cells. Moreover, the predicted structure of EPG5 includes a membrane remodeling domain and a karyopherin-like domain, thus explaining its function as a carrier between separate vesicular compartments. Our findings indicate that EPG5, by controlling nucleic acids intracellular trafficking, links macroautophagy/autophagy to innate and adaptive immunity.


Subject(s)
Adaptive Immunity , Autophagy/immunology , DNA/metabolism , Endosomes/metabolism , Immunity, Innate , Lysosomes/metabolism , Proteins/metabolism , RNA/metabolism , Agenesis of Corpus Callosum/genetics , Agenesis of Corpus Callosum/immunology , Autophagy-Related Proteins , B-Lymphocytes/immunology , Biological Transport , Cataract/genetics , Cataract/immunology , Cell Line , Humans , Lysosomal Membrane Proteins , Mutation , Proteins/genetics , Toll-Like Receptor 9/metabolism , Vesicular Transport Proteins
2.
Cell Death Differ ; 20(5): 774-83, 2013 May.
Article in English | MEDLINE | ID: mdl-23412343

ABSTRACT

Proper regulation of white and brown adipogenic differentiation is important for maintaining an organism's metabolic profile in a homeostatic state. The recent observations showing that the p53 tumor suppressor plays a role in metabolism raise the question of whether it is involved in the regulation of white and brown adipocyte differentiation. By using several in vitro models, representing various stages of white adipocyte differentiation, we found that p53 exerts a suppressive effect on white adipocyte differentiation in both mouse and human cells. Moreover, our in vivo analysis indicated that p53 is implicated in protection against diet-induced obesity. In striking contrast, our data shows that p53 exerts a positive regulatory effect on brown adipocyte differentiation. Abrogation of p53 function in skeletal muscle committed cells reduced their capacity to differentiate into brown adipocytes and histological analysis of brown adipose tissue revealed an impaired morphology in both embryonic and adult p53-null mice. Thus, depending on the specific adipogenic differentiation program, p53 may exert a positive or a negative effect. This cell type dependent regulation reflects an additional modality of p53 in maintaining a homeostatic state, not only in the cell, but also in the organism at large.


Subject(s)
Adipocytes, Brown/metabolism , Adipogenesis , Adipose Tissue, Brown/metabolism , Obesity/metabolism , Tumor Suppressor Protein p53/metabolism , 3T3 Cells , Adipocytes, Brown/cytology , Adipose Tissue, Brown/cytology , Adipose Tissue, White/cytology , Adipose Tissue, White/metabolism , Animals , DNA-Binding Proteins/metabolism , Diet , Energy Metabolism , Humans , Male , Mice , Mice, Inbred C3H , Mice, Knockout , RNA Interference , RNA, Small Interfering , Transcription Factors/metabolism , Tumor Suppressor Protein p53/deficiency , Tumor Suppressor Protein p53/genetics
3.
Cell Death Dis ; 3: e440, 2012 Dec 06.
Article in English | MEDLINE | ID: mdl-23222510

ABSTRACT

The phosphoinositide 3-kinases (PI3Ks) are heterodimers consisting of the catalytic subunit p110 and the regulatory subunit p85. The PI3K/Akt pathway is strongly deregulated in breast cancer (BC) representing one of the mechanisms of resistance to therapies. Therefore, the identification of inhibitors of PI3K components represents one of the main goals to produce therapeutic agents. Here, we evaluated the efficacy of a phosphopeptide 1257 (P-1257) that targeting p85 strongly inhibits PI3K activity. We tested the effects of P-1257 administration in vitro and in vivo using BC cells expressing different levels of ErbB-2 and resistant or responsive to Trastuzumab. We demonstrated that inhibition of p85 activity by P-1257 induces cell death and sensitizes JIMT-1 and KPL-4 ErbB-2-overexpressing BC cells to Trastuzumab treatment. It is noteworthy that P-1257 delivery in vivo by electroporation or liposomes significantly inhibits the proliferation of tumor cells engrafted at subcutaneous and visceral sites. Overall, our data indicate that the p85 subunit is a valid target for therapeutic approaches and suggest that the structure of the peptide used in our study could be utilized for the development of novel drugs to apply in combination with therapies that fail to cure BCs with high PI3K activity.


Subject(s)
Antineoplastic Agents/pharmacology , Breast Neoplasms/enzymology , Down-Regulation , Enzyme Inhibitors/pharmacology , Phosphatidylinositol 3-Kinases/metabolism , Animals , Apoptosis/drug effects , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Catalytic Domain , Female , Humans , Insulin Receptor Substrate Proteins/metabolism , Mice , Mice, SCID , Phosphatidylinositol 3-Kinases/genetics , Phosphoinositide-3 Kinase Inhibitors , Phosphopeptides/pharmacology , Protein Binding/drug effects , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , Receptor, ErbB-3/metabolism
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