Beclin1 Controls the Levels of p53 by Regulating the Deubiquitination Activity of USP10 and USP13

Liu, Junli; Xia, Hongguang; Kim, Minsu; Xu, Lei; Liu, Ying; Zhang, Lihong; Cai, Yu; Norberg, Helin Vakifahmetoglu; Zhang, Tao; Furuya, Tsuyoshi; Jin, Minzhi; Zhu, Zhimin; Wang, Huanchen; Jiao, Yu; Li, Yanxia; Yan, Hao; Choi, Augustine M.K.; Ke, Hengming; Ma, Dawei; Yuan, Junying

doi:10.1016/j.cell.2011.08.037

Cited by 690 publications

(674 citation statements)

References 31 publications

Supporting

Mentioning

626

Contrasting

Unclassified

Order By: Relevance

“…We used spautin-1, which targets BECN1/Beclin 1 for degradation, which fit the data of Martinez et al stating that LAP depends on BECN1. 57,59 In addition, LAP is induced by several stimuli-like ROS, TLR ligands, and PS receptors like TIM4. 60,50 In our model, inhibiting one of these potential LAP-inducing signals might strongly influence LAP with a consequence for Leishmania parasites survival.…”

Section: Discussionmentioning

confidence: 99%

Apoptotic-likeLeishmaniaexploit the host´s autophagy machinery to reduce T-cell-mediated parasite elimination

et al. 2015

View full text Add to dashboard Cite

Apoptosis is a well-defined cellular process in which a cell dies, characterized by cell shrinkage and DNA fragmentation. In parasites like Leishmania, the process of apoptosis-like cell death has been described. Moreover upon infection, the apoptotic-like population is essential for disease development, in part by silencing host phagocytes. Nevertheless, the exact mechanism of how apoptosis in unicellular organisms may support infectivity remains unclear. Therefore we investigated the fate of apoptotic-like Leishmania parasites in human host macrophages. Our data showed-in contrast to viable parasites-that apoptotic-like parasites enter an LC3 C , autophagy-like compartment. The compartment was found to consist of a single lipid bilayer, typical for LC3-associated phagocytosis (LAP). As LAP can provoke anti-inflammatory responses and autophagy modulates antigen presentation, we analyzed how the presence of apoptotic-like parasites affected the adaptive immune response. Macrophages infected with viable Leishmania induced proliferation of CD4 C T-cells, leading to a reduced intracellular parasite survival. Remarkably, the presence of apoptotic-like parasites in the inoculum significantly reduced T-cell proliferation. Chemical induction of autophagy in human monocyte-derived macrophage (hMDM), infected with viable parasites only, had an even stronger proliferationreducing effect, indicating that host cell autophagy and not parasite viability limits the T-cell response and enhances parasite survival. Concluding, our data suggest that apoptotic-like Leishmania hijack the host cells´autophagy machinery to reduce T-cell proliferation. Furthermore, the overall population survival is guaranteed, explaining the benefit of apoptosis-like cell death in a single-celled parasite and defining the host autophagy pathway as a potential therapeutic target in treating Leishmaniasis.

show abstract

Section: Discussionmentioning

confidence: 99%

Apoptotic-likeLeishmaniaexploit the host´s autophagy machinery to reduce T-cell-mediated parasite elimination

et al. 2015

View full text Add to dashboard Cite

show abstract

“…DUBs associated with the ubiquitin-dependent degradative pathway of autophagy largely remain to be elucidated, although USP10 and USP13 have been implicated in the control of the stability of the autophagy gene product BECLIN1 (158).…”

Section: Dubs As Integral Components Of Protein Machineries Assomentioning

confidence: 99%

Deubiquitylases From Genes to Organism

Clague

Barsukov

Coulson

et al. 2013

Physiological Reviews

366

384

View full text Add to dashboard Cite

Ubiquitylation is a major posttranslational modification that controls most complex aspects of cell physiology. It is reversed through the action of a large family of deubiquitylating enzymes (DUBs) that are emerging as attractive therapeutic targets for a number of disease conditions. Here, we provide a comprehensive analysis of the complement of human DUBs, indicating structural motifs, typical cellular copy numbers, and tissue expression profiles. We discuss the means by which specificity is achieved and how DUB activity may be regulated. Generically DUB catalytic activity may be used to 1) maintain free ubiquitin levels, 2) rescue proteins from ubiquitin-mediated degradation, and 3) control the dynamics of ubiquitin-mediated signaling events. Functional roles of individual DUBs from each of five subfamilies in specific cellular processes are highlighted with an emphasis on those linked to pathological conditions where the association is supported by whole organism models. We then specifically consider the role of DUBs associated with protein degradative machineries and the influence of specific DUBs upon expression of receptors and channels at the plasma membrane.

show abstract

“…Recently, a potent small molecule inhibitor of autophagy termed spautin-1 for specific and potent autophagy inhibitor-1 was discovered. 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 [118] . DEPTOR, an inhibitor of mTORC1 and mTORC2, accumulates upon glucose deprivation and mTOR inhibition and induces autophagy [119] .…”

Section: Therapeutic Implications For Autophagy Regulatorsmentioning

confidence: 99%

Application and interpretation of current autophagy inhibitors and activators

et al. 2013

View full text Add to dashboard Cite

Autophagy is the major intracellular degradation system, by which cytoplasmic materials are delivered to and degraded in the lysosome. As a quality control mechanism for cytoplasmic proteins and organelles, autophagy plays important roles in a variety of human diseases, including neurodegenerative diseases, cancer, cardiovascular disease, diabetes and infectious and inflammatory diseases. The discovery of ATG genes and the dissection of the signaling pathways involved in regulating autophagy have greatly enriched our knowledge on the occurrence and development of this lysosomal degradation pathway. In addition to its role in degradation, autophagy may also promote a type of programmed cell death that is different from apoptosis, termed type II programmed cell death. Owing to the dual roles of autophagy in cell death and the specificity of diseases, the exact mechanisms of autophagy in various diseases require more investigation. The application of autophagy inhibitors and activators will help us understand the regulation of autophagy in human diseases, and provide insight into the use of autophagy-targeted drugs. In this review, we summarize the latest research on autophagy inhibitors and activators and discuss the possibility of their application in human disease therapy.

show abstract

Beclin1 Controls the Levels of p53 by Regulating the Deubiquitination Activity of USP10 and USP13

Cited by 690 publications

References 31 publications

Apoptotic-likeLeishmaniaexploit the host´s autophagy machinery to reduce T-cell-mediated parasite elimination

Apoptotic-likeLeishmaniaexploit the host´s autophagy machinery to reduce T-cell-mediated parasite elimination

Deubiquitylases From Genes to Organism

Application and interpretation of current autophagy inhibitors and activators

Contact Info

Product

Resources

About