scholarly journals Activation of acid‐sensing ion channels by carbon dioxide regulates amygdala synaptic protein degradation in memory reconsolidation

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Boren Lin ◽  
Khaled Alganem ◽  
Sinead M. O’Donovan ◽  
Zhen Jin ◽  
FarzanehSadat Naghavi ◽  
...  
Keyword(s):  
Carbon Dioxide ◽  
Ion Channels ◽  
Protein Degradation ◽  
Ampa Receptors ◽  
Memory Retrieval ◽  
Memory Trace ◽  
Ubiquitin Proteasome System ◽  
Calcium Dependent ◽  
Acid Sensing Ion Channels ◽  
Ubiquitin Proteasome

AbstractReconsolidation has been considered a process in which a consolidated memory is turned into a labile stage. Within the reconsolidation window, the labile memory can be either erased or strengthened. Manipulating acid-sensing ion channels (ASICs) in the amygdala via carbon dioxide (CO2) inhalation enhances memory retrieval and its lability within the reconsolidation window. Moreover, pairing CO2 inhalation with retrieval bears the reactivation of the memory trace and enhances the synaptic exchange of the calcium-impermeable AMPA receptors to calcium-permeable AMPA receptors. Our patch-clamp data suggest that the exchange of the AMPA receptors depends on the ubiquitin-proteasome system (UPS), via protein degradation. Ziram (50 µM), a ubiquitination inhibitor, reduces the turnover of the AMPA receptors. CO2 inhalation with retrieval boosts the ubiquitination without altering the proteasome activity. Several calcium-dependent kinases potentially involved in the CO2-inhalation regulated memory liability were identified using the Kinome assay. These results suggest that the UPS plays a key role in regulating the turnover of AMPA receptors during CO2 inhalation.

scholarly journals Transient acidosis while retrieving a fear-related memory enhances its lability

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Jianyang Du ◽  
Margaret P Price ◽  
Rebecca J Taugher ◽  
Daniel Grigsby ◽  
Jamison J Ash ◽  
...  
Keyword(s):  
Ion Channels ◽  
Synaptic Transmission ◽  
Pavlovian Conditioning ◽  
Ampa Receptors ◽  
Memory Trace ◽  
Aversive Event ◽  
Synaptic Signaling ◽  
Acid Sensing Ion Channels ◽  
Labile State ◽  
Conditioning Experiments

Attenuating the strength of fearful memories could benefit people disabled by memories of past trauma. Pavlovian conditioning experiments indicate that a retrieval cue can return a conditioned aversive memory to a labile state. However, means to enhance retrieval and render a memory more labile are unknown. We hypothesized that augmenting synaptic signaling during retrieval would increase memory lability. To enhance synaptic transmission, mice inhaled CO2 to induce an acidosis and activate acid sensing ion channels. Transient acidification increased the retrieval-induced lability of an aversive memory. The labile memory could then be weakened by an extinction protocol or strengthened by reconditioning. Coupling CO2 inhalation to retrieval increased activation of amygdala neurons bearing the memory trace and increased the synaptic exchange from Ca2+-impermeable to Ca2+-permeable AMPA receptors. The results suggest that transient acidosis during retrieval renders the memory of an aversive event more labile and suggest a strategy to modify debilitating memories.

scholarly journals Ccr4 is a novel shuttle factor required for ubiquitin-dependent proteolysis by the 26S proteasome

2020 ◽  
Author(s):  
Ganapathi Kandasamy ◽  
Ashis Kumar Pradhan ◽  
R Palanimurugan
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Protein Degradation ◽  
Ubiquitin Proteasome System ◽  
Proteasomal Degradation ◽  
Rna Degradation ◽  
26S Proteasome ◽  
Cellular Proteins ◽  
Cellular Homeostasis ◽  
Substrate Degradation ◽  
Ubiquitin Proteasome

AbstractDegradation of short-lived and abnormal proteins are essential for normal cellular homeostasis. In eukaryotes, such unstable cellular proteins are selectively degraded by the ubiquitin proteasome system (UPS). Furthermore, abnormalities in protein degradation by the UPS have been linked to several human diseases. Ccr4 protein is a known component of the Ccr4-Not complex, which has established roles in transcription, mRNA de-adenylation and RNA degradation etc. Excitingly in this study, we show that Ccr4 protein has a novel function as a shuttle factor that promotes ubiquitin-dependent degradation of short-lived proteins by the 26S proteasome. Using a substrate of the well-studied ubiquitin fusion degradation (UFD) pathway, we found that its UPS-mediated degradation was severely impaired upon deletion of CCR4 in Saccharomyces cerevisiae. Additionally, we show that Ccr4 binds to cellular ubiquitin conjugates and the proteasome. In contrast to Ccr4, most other subunits of the Ccr4-Not complex proteins are dispensable for UFD substrate degradation. From our findings we conclude that Ccr4 functions in the UPS as a shuttle factor targeting ubiquitylated substrates for proteasomal degradation.

scholarly journals E2A protein degradation by the ubiquitin-proteasome system is stage-dependent during muscle differentiation

Oncogene ◽  
2006 ◽  
Vol 26 (3) ◽  
pp. 441-448 ◽  
Author(s):  
L Sun ◽  
J S Trausch-Azar ◽  
A Ciechanover ◽  
A L Schwartz
Keyword(s):  
Protein Degradation ◽  
Ubiquitin Proteasome System ◽  
Muscle Differentiation ◽  
Ubiquitin Proteasome

scholarly journals Involvement of the Ubiquitin-Proteasome System in the Formation of Experimental Postsurgical Peritoneal Adhesions

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Clara Di Filippo ◽  
Pasquale Petronella ◽  
Fulvio Freda ◽  
Marco Scorzelli ◽  
Marco Ferretti ◽  
...  
Keyword(s):  
Protein Degradation ◽  
Ubiquitin Proteasome System ◽  
20S Proteasome ◽  
Intracellular Protein ◽  
Peritoneal Adhesions ◽  
Proteasome Subunit ◽  
Peritoneal Tissue ◽  
Intracellular Protein Degradation ◽  
Ubiquitin Proteasome

We investigated the Ubiquitin-Proteasome System (UPS), major nonlysosomal intracellular protein degradation system, in the genesis of experimental postsurgical peritoneal adhesions. We assayed the levels of UPS within the adhered tissue along with the development of peritoneal adhesions and used the specific UPS inhibitor bortezomib in order to assess the effect of the UPS blockade on the peritoneal adhesions. We found a number of severe postsurgical peritoneal adhesions at day 5 after surgery increasing until day 10. In the adhered tissue an increased values of ubiquitin and the 20S proteasome subunit, NFkB, IL-6, TNF-αand decreased values of IkB-beta were found. In contrast, bortezomib-treated rats showed a decreased number of peritoneal adhesions, decreased values of ubiquitin and the 20S proteasome, NFkB, IL-6, TNF-α, and increased levels of IkB-beta in the adhered peritoneal tissue. The UPS system, therefore, is primarily involved in the formation of post-surgical peritoneal adhesions in rats.

scholarly journals CCR4-NOT complex nuclease Caf1 is a novel shuttle factor involved in the degradation of ubiquitin-modified proteins by 26S proteasome

2020 ◽  
Author(s):  
Ganapathi Kandasamy ◽  
Ashis Kumar Pradhan ◽  
R Palanimurugan
Keyword(s):  
Protein Degradation ◽  
Translational Control ◽  
Ubiquitin Proteasome System ◽  
26S Proteasome ◽  
Control Mechanisms ◽  
Gene Expressions ◽  
Proteolytic Pathway ◽  
Ubiquitin Ligase E3 ◽  
Ubiquitin Proteasome ◽  
Modified Proteins

AbstractProtein degradation by ubiquitin proteasome system (UPS) is the major selective proteolytic pathway responsible for the degradation of short lived proteins ranging from regulatory proteins to abnormal proteins. Many diseases are associated with abnormal protein degradation; occasionally such dysregulated protein degradation is compensated by various transcriptional and translational control mechanisms in the cell. Among those pathways CCR4-NOT protein complex is responsible for transcriptional and transitional control of various gene expressions. Furthermore, CCR4-NOT complex also has a RING type ubiquitin ligase (E3) which is required for the degradation of several proteins. Here we report a novel function that the CCR4-NOT complex 3’-5’ exonuclease Caf1 is involved in ubiquitindependent degradation of short lived proteins by the 26S proteasome in yeast Saccharomyces cerevisiae. caf1 deletion results in stabilization of R-Ura3 (N-end rule) and Ub-V76-Ura3 (Ubiquitin fusion degradation) substrates from proteasomal degradation. Additionally, caf1 deletion accumulates ubiquitin-modified Ub-V76-Ura3 proteins and Caf1 binds to poly-ubiquitin conjugates and linear tetra ubiquitin chains. Surprisingly, Caf1 interacts with 19S regulatory particle complex of the 26S proteasome. Therefore, we conclude that Caf1 has an exciting novel function as an ubiquitin shuttle factor in which Caf1 targets ubiquitin-modified proteins to 26S proteasome for efficient degradation.

scholarly journals Ubiquitin receptors are required for substrate-mediated activation of the proteasome’s unfolding ability

2019 ◽  
Author(s):  
Mary D. Cundiff ◽  
Christina M. Hurley ◽  
Jeremy D. Wong ◽  
Aarti Bashyal ◽  
Jake Rosenberg ◽  
...  
Keyword(s):  
Protein Degradation ◽  
Motor Proteins ◽  
Ubiquitin Proteasome System ◽  
Physical Models ◽  
Protein Domain ◽  
Eukaryotic Cells ◽  
Multiple Receptors ◽  
Ubiquitin Proteasome ◽  
Ubiquitin Receptors ◽  
Partial Redundancy

ABSTRACTThe ubiquitin-proteasome system (UPS) is responsible for the bulk of protein degradation in eukaryotic cells, but the factors that cause different substrates to be unfolded and degraded to different extents are still poorly understood. We previously showed that polyubiquitinated substrates were degraded with greater processivity (with a higher tendency to be unfolded and degraded than released) than ubiquitin-independent substrates. Thus, even though ubiquitin chains are removed before unfolding and degradation occur, they affect the unfolding of a protein domain. How do ubiquitin chains activate the proteasome’s unfolding ability? We investigated the roles of the three intrinsic proteasomal ubiquitin receptors - Rpn1, Rpn10 and Rpn13 - in this activation. We find that these receptors are required for substrate-mediated activation of the proteasome’s unfolding ability. Rpn13 plays the largest role, but there is also partial redundancy between receptors. The architecture of substrate ubiquitination determines which receptors are needed for maximal unfolding ability, and, in some cases, simultaneous engagement of ubiquitin by multiple receptors may be required. Our results suggest physical models for how ubiquitin receptors communicate with the proteasomal motor proteins.

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