p62 links the autophagy pathway and the ubiqutin–proteasome system upon ubiquitinated protein degradation

Liu, Wei Jing; Ye, Lin; Huang, Wei; Guo, Lanting; Xu, Zi Gan; Wu, Hong; Yang, Chen; Liu, Hua Feng

doi:10.1186/s11658-016-0031-z

Cited by 660 publications

(559 citation statements)

References 95 publications

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“…It has been proposed that the presence of neo-epitopes on CA is related to the removal of these bodies via the natural immune system after their extrusion (Augé et al, 2017). In this regard, here we show that CAL granules contain p62 protein, which has a ubiquitin-binding domain and is involved in the sequestration of ubiquitinated proteins and organelles (Liu et al, 2016). Also, p62 is related to secretory autophagy, a process in which the content of the autophagosome extrudes from the cell (Ponpuak et al, 2016).…”

Section: Discussionmentioning

confidence: 78%

Astrocytes and neurons produce distinct types of polyglucosan bodies in Lafora disease

Augé

Pelegrí

Manich

et al. 2018

Glia

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Lafora disease (LD), the most devastating adolescence-onset epilepsy, is caused by mutations in the EPM2A or EPM2B genes, which encode the proteins laforin and malin, respectively. Loss of function of one of these proteins, which are involved in the regulation of glycogen synthesis, induces the accumulation of polyglucosan bodies (PGBs)-known as Lafora bodies (LBs) and associated with neurons-in the brain. Ageing and some neurodegenerative conditions lead to the appearance of another type of PGB called corpora amylacea, which are associated with astrocytes and contain neo-epitopes that can be recognized by natural antibodies. Here we studied the PGBs in the cerebral cortex and hippocampus of malin knockout mice, a mouse model of LD. These animals presented not only LBs associated with neurons but also a significant number of PGBs associated with astrocytes. These astrocytic PGBs were also increased in mice from senescence-accelerated mouse-prone 8 (SAMP8) strain and mice with overexpression of Protein Targeting to Glycogen (PTG ), indicating that they are not exclusive of LD. The astrocytic PGBs, but not neuronal LBs, contained neo-epitopes that are recognized by natural antibodies. The astrocytic PGBs appeared predominantly in the hippocampus but were also present in some cortical brain regions, while neuronal LBs were found mainly in the brain cortex and the pyramidal layer of hippocampal regions CA2 and CA3. Our results indicate that astrocytes, contrary to current belief, are involved in the etiopathogenesis of LD.

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Section: Discussionmentioning

confidence: 78%

Astrocytes and neurons produce distinct types of polyglucosan bodies in Lafora disease

Augé

Pelegrí

Manich

et al. 2018

Glia

View full text Add to dashboard Cite

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“…Therefore, the ratio of LC3-Ⅱ to LC3-Ⅰ will become larger when the quantity of autophagosomes increases (7). In addition to the shift of LC3-Ⅰ to LC3-Ⅱ, another crucial ATG protein P62 that interacts with ubiquitinated proteins through its UBA domain (ubiquitin-associated domain) and then delivers them to LC3-Ⅱ via another domain LIR (LC3-interacting region) will be finally degraded in the autolysosome, so the level of P62 has a contrary relationship with autophagic activity (8).…”

Section: Introductionmentioning

confidence: 99%

Differences of basic and induced autophagic activity between K562 and K562/ADM cells

Wang

Chen

Zhang

et al. 2017

IRDR

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“…Many proteins are degraded by both autophagosome and the proteasome [55]. Proteasomal degradation of NOXA has been extensively studied [56].…”

Section: Discussionmentioning

confidence: 99%

Cyclin D1-CDK4 activity drives sensitivity to bortezomib in mantle cell lymphoma by blocking autophagy-mediated proteolysis of NOXA

et al. 2018

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BackgroundMantle cell lymphoma (MCL) is an aggressive B-non-Hodgkin lymphoma with generally poor outcome. MCL is characterized by an aberrantly high cyclin D1-driven CDK4 activity. New molecular targeted therapies such as inhibitors of the ubiquitin-proteasome system (UPS) have shown promising results in preclinical studies and MCL patients. Our previous research revealed stabilization of the short-lived pro-apoptotic NOXA as a critical determinant for sensitivity to these inhibitors. It is currently unclear how cyclin D1 overexpression and aberrant CDK4 activity affect NOXA stabilization and treatment efficacy of UPS inhibitors in MCL.MethodsThe effect of cyclin D1-driven CDK4 activity on response of MCL cell lines and primary cells to proteasome inhibitor treatment was investigated using survival assays (Flow cytometry, AnnexinV/PI) and Western blot analysis of NOXA protein. Half-life of NOXA protein was determined by cycloheximide treatment and subsequent Western blot analysis. The role of autophagy was analyzed by LC3-II protein expression and autophagolysosome detection. Furthermore, silencing of autophagy-related genes was performed using siRNA and MCL cells were treated with autophagy inhibitors in combination with proteasome and CDK4 inhibition.ResultsIn this study, we show that proteasome inhibitor-mediated cell death in MCL depends on cyclin D1-driven CDK4 activity. Inhibition of cyclin D1/CDK4 activity significantly reduced proteasome inhibitor-mediated stabilization of NOXA protein, mainly driven by an autophagy-mediated proteolysis. Bortezomib-induced cell death was significantly potentiated by compounds that interfere with autophagosomal function. Combined treatment with bortezomib and autophagy inhibitors enhanced NOXA stability leading to super-induction of NOXA protein. In addition to established autophagy modulators, we identified the fatty acid synthase inhibitor orlistat to be an efficient autophagy inhibitor when used in combination with bortezomib. Accordingly, this combination synergistically induced apoptosis both in MCL cell lines and in patient samples.ConclusionOur data demonstrate that CDK4 activity in MCL is critical for NOXA stabilization upon treatment with UPS inhibitors allowing preferential induction of cell death in cyclin D transformed cells. Under UPS blocked conditions, autophagy appears as the critical regulator of NOXA induction. Therefore, inhibitors of autophagy are promising candidates to increase the activity of proteasome inhibitors in MCL.Electronic supplementary materialThe online version of this article (10.1186/s13045-018-0657-6) contains supplementary material, which is available to authorized users.

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p62 links the autophagy pathway and the ubiqutin–proteasome system upon ubiquitinated protein degradation

Cited by 660 publications

References 95 publications

Astrocytes and neurons produce distinct types of polyglucosan bodies in Lafora disease

Astrocytes and neurons produce distinct types of polyglucosan bodies in Lafora disease

Differences of basic and induced autophagic activity between K562 and K562/ADM cells

Cyclin D1-CDK4 activity drives sensitivity to bortezomib in mantle cell lymphoma by blocking autophagy-mediated proteolysis of NOXA

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