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Wild-type P53 proteolytic inactivation by asparagine endopeptidase promotes glioblastoma progression

ABSTRACT: A comparison of expression changes between AEP RNAi and U87 control cell lines

ORGANISM(S): Homo sapiens

PROVIDER: GSE104806 | GEO | 2019/10/01

REPOSITORIES: GEO

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Wild-type P53 proteolytic inactivation by asparagine endopeptidase promotes glioblastoma progression

Project description:Wild-type P53 proteolytic inactivation by asparagine endopeptidase promotes glioblastoma progression

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PD-1 through asparaginyl endopeptidase regulates FoxP3 Stability in Induced Regulatory T cells

Project description:CD4+ T cell differentiation into multiple T helper lineages is critical for optimal adaptive immune responses. This report identified a novel intrinsic mechanism by which PD-1 signaling imparted regulatory phenotype to FoxP3+ Th1 cells (denoted as Tbet+iTregPDL1 cells) and iTregs. Tbet+iTregPDL1 cells were capable of preventing inflammation in murine models of experimental colitis and experimental graft versus host disease. PDL-1 binding to PD-1 imparted regulatory function to Tbet+iTregPDL1 cells and iTregs by specifically downregulating an endolysosomal protease asparaginyl endopeptidase (AEP) AEP regulated FoxP3 stability and blocking AEP imparted regulatory function in Tbet+iTregs cells. Also AEP-/- iTregs significantly inhibited GvHD and maintained FoxP3. Furthermore, PD-1 mediated FoxP3 maintenance in Tbet+Th1 cells occurred both in tumor infiltrating lymphocytes (TIL) and during chronic viral infection. Collectively, this report has identified a novel intrinsic function for PD-1 in converting Th1 cells into Tregs through an intrinsic proteolytic pathway

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Understanding the physiological role of asparaginyl endopeptidase (AEP)/Legumain

Project description:Understanding the regulation of lysosomal proteolytic/hidrolytic capacity has been recently advanced in a huge manner by the discovery of the lysosome-mTOR-TFEB pathway connecting nutrient sensing, autophagy and de novo lysosome generation. But, how lysosomes can adjust their proteolytic/hidrolytic capacity to meet varying conditions (more or less substrate) under normal fed conditions is not known. We have used AEP as a proxy to understand how lysosomes can compensate the lack of a key lysosomal protease to meet the requirements under physiological, fed conditions. To do this, we did compare cytoplasmic, membrane and nuclear fractions of WT and AEP MEFs that were expanded in SILAC media. AEP knock-out mice show pale kidney, with abnormal proliferation of the epithelial proximal tubular cells. In an attempt to understand the role of AEP in the kidney, we did compare kidney obtained from WT and AEP mice using kidneys from WT mice that were fed with SILAC food. Also, in an attempt to reproduce the changes observed in the absence of AEP in kidney and MEFs, we treated WT MEFs grown in SILAC media with MVO26630, specific inhibitor of AEP, for 12 and 48 hours.

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Differential effects of estrogen receptor beta isoforms on glioblastoma progression

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