scholarly journals p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death

2005 ◽  
Vol 171 (4) ◽  
pp. 603-614 ◽  
Author(s):  
Geir Bjørkøy ◽  
Trond Lamark ◽  
Andreas Brech ◽  
Heidi Outzen ◽  
Maria Perander ◽  
...  
Keyword(s):  
Cell Death ◽  
Protective Effect ◽  
Cell Survival ◽  
Light Chain ◽  
Protein Aggregates ◽  
Mutant Huntingtin ◽  
Ubiquitinated Protein ◽  
Protein Levels ◽  
Autophagic Degradation ◽  
Starvation Conditions

Autophagic degradation of ubiquitinated protein aggregates is important for cell survival, but it is not known how the autophagic machinery recognizes such aggregates. In this study, we report that polymerization of the polyubiquitin-binding protein p62/SQSTM1 yields protein bodies that either reside free in the cytosol and nucleus or occur within autophagosomes and lysosomal structures. Inhibition of autophagy led to an increase in the size and number of p62 bodies and p62 protein levels. The autophagic marker light chain 3 (LC3) colocalized with p62 bodies and coimmunoprecipitated with p62, suggesting that these two proteins participate in the same complexes. The depletion of p62 inhibited recruitment of LC3 to autophagosomes under starvation conditions. Strikingly, p62 and LC3 formed a shell surrounding aggregates of mutant huntingtin. Reduction of p62 protein levels or interference with p62 function significantly increased cell death that was induced by the expression of mutant huntingtin. We suggest that p62 may, via LC3, be involved in linking polyubiquitinated protein aggregates to the autophagy machinery.

scholarly journals TRAF3 regulates the oncogenic proteins Pim2 and c-Myc to restrain survival in normal and malignant B cells

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Amy L. Whillock ◽  
Nurbek Mambetsariev ◽  
Wai W. Lin ◽  
Laura L. Stunz ◽  
Gail A. Bishop
Keyword(s):  
Cell Death ◽  
B Cells ◽  
B Cell ◽  
Cell Survival ◽  
Cell Lines ◽  
Adapter Protein ◽  
Protein Levels ◽  
B Cell Survival ◽  
Multiple Context ◽  
Context Specific

Abstract TRAF3 is a versatile intracellular adapter protein with multiple context-specific roles. Uniquely in B cells, TRAF3 deficiency enhances survival and increases the risk of transformation, as loss of TRAF3 is observed in several types of B cell cancers. Here, we report a new mechanism for TRAF3 in the restraint of B cell survival. We found that TRAF3 deficiency was associated with induction of the pro-survival kinase Pim2 in mouse primary B cells and human malignant B cell lines. The increase in Pim2 was independent of NF-κB2 activation but was ameliorated with inhibition of STAT3 expression or function. TRAF3 deficiency also led to a Pim2-dependent increase in c-Myc protein levels and was associated with reduced c-Myc ubiquitination. TRAF3-deficient primary B cells were less sensitive to cell death induced by the Pim inhibitors SGI-1776 and TP-3654. Interestingly, human malignant B cell lines with low expression of TRAF3 were more sensitive to Pim inhibition-induced cell death. Combination treatment of TRAF3-deficient B cells and B cell tumor lines with c-Myc inhibitors enhanced their sensitivity to Pim inhibition, suggesting a possible therapeutic strategy. TRAF3 thus suppresses a Pim2-mediated B cell survival axis, which can be a potential target for treatment of B cell malignancies.

scholarly journals Functional multivesicular bodies are required for autophagic clearance of protein aggregates associated with neurodegenerative disease

2007 ◽  
Vol 179 (3) ◽  
pp. 485-500 ◽  
Author(s):  
Maria Filimonenko ◽  
Susanne Stuffers ◽  
Camilla Raiborg ◽  
Ai Yamamoto ◽  
Lene Malerød ◽  
...  
Keyword(s):  
Multivesicular Body ◽  
Protein Aggregates ◽  
Multivesicular Bodies ◽  
Ubiquitinated Protein ◽  
Endosomal Sorting ◽  
Ubiquitinated Proteins ◽  
Protein Deposits ◽  
Autophagic Degradation ◽  
Lateral Sclerosis ◽  
In Cells

The endosomal sorting complexes required for transport (ESCRTs) are required to sort integral membrane proteins into intralumenal vesicles of the multivesicular body (MVB). Mutations in the ESCRT-III subunit CHMP2B were recently associated with frontotemporal dementia and amyotrophic lateral sclerosis (ALS), neurodegenerative diseases characterized by abnormal ubiquitin-positive protein deposits in affected neurons. We show here that autophagic degradation is inhibited in cells depleted of ESCRT subunits and in cells expressing CHMP2B mutants, leading to accumulation of protein aggregates containing ubiquitinated proteins, p62 and Alfy. Moreover, we find that functional MVBs are required for clearance of TDP-43 (identified as the major ubiquitinated protein in ALS and frontotemporal lobar degeneration with ubiquitin deposits), and of expanded polyglutamine aggregates associated with Huntington's disease. Together, our data indicate that efficient autophagic degradation requires functional MVBs and provide a possible explanation to the observed neurodegenerative phenotype seen in patients with CHMP2B mutations.

scholarly journals At the Crossroads: Mechanisms of Apoptosis and Autophagy in Cell Life and Death

Acta Naturae ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 106-115
Author(s):  
Viktoriia L. Shliapina ◽  
Sofia V. Yurtaeva ◽  
Maria P. Rubtsova ◽  
Olga A. Dontsova
Keyword(s):  
Cell Death ◽  
Neurodegenerative Disease ◽  
Cell Survival ◽  
Signaling Pathways ◽  
Molecular Interactions ◽  
Protein Aggregates ◽  
The Body ◽  
Life And Death ◽  
Cell Life ◽  
Minimal Damage

Apoptosis and autophagy are conserved processes that regulate cell survival and death under stress conditions. real rolex submariner vs fake Apoptosis aims to remove cells from the body with minimal damage to surrounding tissues. Autophagy promotes removal of damaged organelles, protein aggregates, and cellular pathogens, stimulating cell survival. The signaling pathways involved in the regulation of apoptosis and autophagy largely overlap, leading to both competition and unidirectional interaction, which is of particular interest in investigating them as potential targets for cancer, paul newman rolex replica for saleautoimmune, and neurodegenerative disease therapies. This review analyzes the main pathways of molecular interactions between autophagy and apoptosis, which is necessary for understanding the mechanism maintaining rolex iced out fake the balance between cell death and survival under unfavorable conditions.

scholarly journals Flavin Oxidase-Induced ROS Generation Modulates PKC Biphasic Effect of Resveratrol on Endothelial Cell Survival

Biomolecules ◽  
2019 ◽  
Vol 9 (6) ◽  
pp. 209 ◽  
Author(s):  
Anna Maria Posadino ◽  
Roberta Giordo ◽  
Annalisa Cossu ◽  
Gheyath K. Nasrallah ◽  
Abdullah Shaito ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Dna Synthesis ◽  
Cell Survival ◽  
Cellular Response ◽  
Cell Cycle Progression ◽  
Natural Antioxidants ◽  
Cycle Progression ◽  
Protein Levels ◽  
The Impact

Background: Dietary intake of natural antioxidants is thought to impart protection against oxidative-associated cardiovascular diseases. Despite many in vivo studies and clinical trials, this issue has not been conclusively resolved. Resveratrol (RES) is one of the most extensively studied dietary polyphenolic antioxidants. Paradoxically, we have previously demonstrated that high RES concentrations exert a pro-oxidant effect eventually elevating ROS levels leading to cell death. Here, we further elucidate the molecular determinants underpinning RES-induced oxidative cell death. Methods: Using human umbilical vein endothelial cells (HUVECs), the effect of increasing concentrations of RES on DNA synthesis and apoptosis was studied. In addition, mRNA and protein levels of cell survival or apoptosis genes, as well as protein kinase C (PKC) activity were determined. Results: While high concentrations of RES reduce PKC activity, inhibit DNA synthesis and induce apoptosis, low RES concentrations elicit an opposite effect. This biphasic concentration-dependent effect (BCDE) of RES on PKC activity is mirrored at the molecular level. Indeed, high RES concentrations upregulate the proapoptotic Bax, while downregulating the antiapoptotic Bcl-2, at both mRNA and protein levels. Similarly, high RES concentrations downregulate the cell cycle progression genes, c-myc, ornithine decarboxylase (ODC) and cyclin D1 protein levels, while low RES concentrations display an increasing trend. The BCDE of RES on PKC activity is abrogated by the ROS scavenger Tempol, indicating that this enzyme acts downstream of the RES-elicited ROS signaling. The RES-induced BCDE on HUVEC cell cycle machinery was also blunted by the flavin inhibitor diphenyleneiodonium (DPI), implicating flavin oxidase-generated ROS as the mechanistic link in the cellular response to different RES concentrations. Finally, PKC inhibition abrogates the BCDE elicited by RES on both cell cycle progression and pro-apoptotic gene expression in HUVECs, mechanistically implicating PKC in the cellular response to different RES concentrations. Conclusions: Our results provide new molecular insight into the impact of RES on endothelial function/dysfunction, further confirming that obtaining an optimal benefit of RES is concentration-dependent. Importantly, the BCDE of RES could explain why other studies failed to establish the cardio-protective effects mediated by natural antioxidants, thus providing a guide for future investigation looking at cardio-protection by natural antioxidants.

Dysregulation of H11 Kinase in the Failing Left Ventricular Myocardium

2019 ◽  
pp. 1-5
Keyword(s):  
Cell Death ◽  
Cell Survival ◽  
Sodium Dodecyl ◽  
Left Ventricular ◽  
Idiopathic Dilated Cardiomyopathy ◽  
Left Ventricular Myocardium ◽  
Human Donor ◽  
Protein Levels ◽  
Lv Dysfunction ◽  
Mitochondrial Fractions

Background: Increased expression of H11 kinase (H11K) has been observed in Left Ventricular (LV) myocardium of failed human hearts. Its potential role as a contributor to the progression of Heart Failure (HF) remains uncertain. In the present study we examined the expression of H11K in cytosolic and mitochondrial fractions of failing human and dog LV myocardium and assessed its interaction with Akt (cell-survival enzyme) and p38MAPK (programmed cell death enzyme). Methods: Total RNA and Sodium-Dodecyl Sulfate (SDS) extracts were prepared from homogenate of LV specimens of 6 dogs with intracoronary microembolization-induced HF, 6 normal (NL) dogs, 7 explanted failed human hearts due to Idiopathic Dilated Cardiomyopathy (IDC), 7 failed human hearts due to Ischemic Cardiomyopathy (ICM) and 7 non-failing human donor hearts (DNR). SDS extracts were also prepared from cytosolic and mitochondrial fractions isolated from LV specimens. Results: H11K mRNA and protein levels normalized to GAPDH increased significantly in LV tissue from ICM and IDC hearts compared to DNR hearts and in HF dogs compared with NL dogs. H11K protein levels increased in cytosolic fractions but decreased in mitochondrial fractions of both failed human and dog hearts compared to DNR hearts and NL dog hearts. Immunoprecipitation studies in specimens from HF dogs showed that H11K cytosolic fractions interacted predominantly with p38MAPK and least with Akt when compared with NL dogs. Conclusions: Enhanced interaction of H11K with p38MAPK in HF can promote cell death thus contributing to progressive LV dysfunction. Therapeutic modalities that restore interaction of H11K with Akt and augment H11K translocation to mitochondria can potentially and partially reverse the progression of LV dysfunction by promoting cell survival.

scholarly journals Phagocytic glia are obligatory intermediates in transmission of mutant huntingtin aggregates across neuronal synapses

2019 ◽  
Author(s):  
Kirby M. Donnelly ◽  
Olivia R. DeLorenzo ◽  
Aprem D.A. Zaya ◽  
Gabrielle E. Pisano ◽  
Wint M. Thu ◽  
...  
Keyword(s):  
Cell Death ◽  
Neuronal Activity ◽  
Huntington Disease ◽  
Olfactory System ◽  
Scavenger Receptor ◽  
Protein Aggregates ◽  
Synaptic Dysfunction ◽  
Mutant Huntingtin ◽  
Neuronal Synapses ◽  
The Brain

ABSTRACTEmerging evidence supports the hypothesis that pathogenic protein aggregates associated with neurodegenerative diseases spread from cell to cell through the brain in a manner akin to infectious prions. Here, we show that mutant huntingtin (mHtt) aggregates associated with Huntington disease transfer anterogradely from presynaptic to postsynaptic neurons in the adult Drosophila olfactory system. Trans-synaptic transmission of mHtt aggregates is inversely correlated with neuronal activity and blocked by inhibiting caspases in presynaptic neurons, implicating synaptic dysfunction and cell death in aggregate spreading. Remarkably, mHtt aggregate transmission across synapses requires the glial scavenger receptor Draper and involves a transient visit to the glial cytoplasm, indicating that phagocytic glia act as obligatory intermediates in aggregate spreading between synaptically-connected neurons. These findings expand our understanding of phagocytic glia as double-edged players in neurodegeneration—by clearing neurotoxic protein aggregates, but also providing an opportunity for prion-like seeds to evade phagolysosomal degradation and propagate further in the brain.

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