Dataset Information

Beclin1 controls the levels of p53 by regulating the deubiquitination activity of USP10 and USP13.

ABSTRACT: Autophagy is an important intracellular catabolic mechanism that mediates the degradation of cytoplasmic proteins and organelles. We report a potent small molecule inhibitor of autophagy named "spautin-1" for specific and potent autophagy inhibitor-1. Spautin-1 promotes the degradation of Vps34 PI3 kinase complexes by inhibiting two ubiquitin-specific peptidases, USP10 and USP13, that target the Beclin1 subunit of Vps34 complexes. Beclin1 is a tumor suppressor and frequently monoallelically lost in human cancers. Interestingly, Beclin1 also controls the protein stabilities of USP10 and USP13 by regulating their deubiquitinating activities. Since USP10 mediates the deubiquitination of p53, regulating deubiquitination activity of USP10 and USP13 by Beclin1 provides a mechanism for Beclin1 to control the levels of p53. Our study provides a molecular mechanism involving protein deubiquitination that connects two important tumor suppressors, p53 and Beclin1, and a potent small molecule inhibitor of autophagy as a possible lead compound for developing anticancer drugs.

SUBMITTER: Liu J

PROVIDER: S-EPMC3441147 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Beclin1 controls the levels of p53 by regulating the deubiquitination activity of USP10 and USP13.

Liu Junli J Xia Hongguang H Kim Minsu M Xu Lihua L Li Ying Y Zhang Lihong L Cai Yu Y Norberg Helin Vakifahmetoglu HV Zhang Tao T Furuya Tsuyoshi T Jin Minzhi M Zhu Zhimin Z Wang Huanchen H Yu Jia J Li Yanxia Y Hao Yan Y Choi Augustine A Ke Hengming H Ma Dawei D Yuan Junying J

Cell 20110901 1

Autophagy is an important intracellular catabolic mechanism that mediates the degradation of cytoplasmic proteins and organelles. We report a potent small molecule inhibitor of autophagy named "spautin-1" for specific and potent autophagy inhibitor-1. Spautin-1 promotes the degradation of Vps34 PI3 kinase complexes by inhibiting two ubiquitin-specific peptidases, USP10 and USP13, that target the Beclin1 subunit of Vps34 complexes. Beclin1 is a tumor suppressor and frequently monoallelically lost ...[more]

PMID: 21962518

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Project description:BackgroundNOD-like receptors affect multiple stages of cancer progression in many malignancies. NACHT, LRR, and PYD domain-containing protein 7 (NLRP7) is a member of the NOD-like receptor family, although its role in tumorigenesis remains unclear. By analyzing clinical samples, we found that NLRP7 protein levels were upregulated in colorectal cancer (CRC). We proposed the hypothesis that a high level of NLRP7 in CRC may promote tumor progression. Here, we further investigated the role of NLRP7 in CRC and the underlying mechanism.MethodsNLRP7 expression in human CRC and adjacent non-tumorous tissues was examined by quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, and immunohistochemistry. The effect of NLRP7 in CRC progression was investigated in vitro and in vivo. Proteins interacting with NLRP7 were identified by immunoprecipitation and mass spectrometry analysis while immunofluorescence staining revealed the cellular location of the proteins. Cellular ubiquitination and protein stability assays were applied to demonstrate the ubiquitination effect on NLRP7. Cloning and mutagenesis were used to identify a lysine acceptor site that mediates NLRP7 ubiquitination. Cytokines/chemokines affected by NLRP7 were identified by RNA sequencing, qRT-PCR, and enzyme-linked immunosorbent assay. Macrophage phenotypes were determined using qRT-PCR, flow cytometry, and immunohistochemistry.ResultsNLRP7 protein levels, but not mRNA levels, were upregulated in CRC, and increased NLRP7 protein expression was associated with poor survival. NLRP7 promoted tumor cell proliferation and metastasis in vivo and in vitro and interacted with ubiquitin-specific protease 10, which catalyzed its deubiquitination in CRC cells. NLRP7 stability and protein levels in CRC cells were modulated by ubiquitination and deubiquitination, and NLRP7 was involved in the ubiquitin-specific protease 10 promotion of tumor progression and metastasis in CRC. K379 was an important lysine acceptor site that mediates NLRP7 ubiquitination in CRC cells. In CRC, NLRP7 promoted the polarization of pro-tumor M2-like macrophages by inducing the secretion of C-C motif chemokine ligand 2. Furthermore, NLRP7 promoted NF-κB nuclear translocation and activation of C-C motif chemokine ligand 2 transcription.ConclusionsWe showed that NLRP7 promotes CRC progression and revealed an as-yet-unidentified mechanism by which NLRP7 induces the polarization of pro-tumor M2-like macrophages. These results suggest that NLRP7 could serve as a biomarker and novel therapeutic target for the treatment of CRC.

Project description:LpxC is a deacetylase that catalyzes the first committed step of lipid A biosynthesis in Escherichia coli LpxC competes for a common precursor, R-3-hydroxymyristoyl-UDP-GlcNAc, with FabZ, whose dehydratase activity catalyzes the first committed step of phospholipid biosynthesis. To maintain the optimum flow of the common precursor to these two competing pathways, the LpxC level is controlled by FtsH/YciM-mediated proteolysis. It is not known whether this complex or another protein senses the status of lipid A synthesis to control LpxC proteolysis. The work carried out in this study began with a novel mutation, yejM1163, which causes hypersensitivity to large antibiotics such as vancomycin and erythromycin. Isolates resistant to these antibiotics carried suppressor mutations in the ftsH and yciM genes. Western blot analysis showed a dramatically reduced LpxC level in the yejM1163 background, while the presence of ftsH or yciM suppressor mutations restored LpxC levels to different degrees. Based on these observations, it is proposed that YejM is a sensor of lipid A synthesis and controls LpxC levels by modulating the activity of the FtsH/YciM complex. The truncation of the periplasmic domain in the YejM1163 protein causes unregulated proteolysis of LpxC, thus diverting a greater pool of R-3-hydroxymyristoyl-UDP-GlcNAc toward phospholipid synthesis. This imbalance in lipid synthesis perturbs the outer membrane permeability barrier, causing hypersensitivity toward vancomycin and erythromycin. yejM1163 suppressor mutations in ftsH and yciM lower the proteolytic activity toward LpxC, thus restoring lipid homeostasis and the outer membrane permeability barrier.IMPORTANCE Lipid homeostasis is critical for proper envelope functions. The level of LpxC, which catalyzes the first committed step of lipopolysaccharide (LPS) synthesis, is controlled by an essential protease complex comprised of FtsH and YciM. Work carried out here suggests YejM, an essential envelope protein, plays a central role in sensing the state of LPS synthesis and controls LpxC levels by regulating the activity of FtsH/YciM. All four essential proteins are attractive targets of therapeutic development.

Dataset Information

Beclin1 controls the levels of p53 by regulating the deubiquitination activity of USP10 and USP13.

Publications

Beclin1 controls the levels of p53 by regulating the deubiquitination activity of USP10 and USP13.

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