scholarly journals N-Acyldopamine induces aggresome formation without proteasome inhibition and enhances protein aggregation via p62/SQSTM1 expression

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Gen Matsumoto ◽  
Tomonao Inobe ◽  
Takanori Amano ◽  
Kiyohito Murai ◽  
Nobuyuki Nukina ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Proteasome Inhibition ◽  
Aggresome Formation

scholarly journals The p97-UBXN1 complex regulates aggresome formation

2020 ◽  
Author(s):  
Sirisha Mukkavalli ◽  
Jacob Aaron Klickstein ◽  
Betty Ortiz ◽  
Peter Juo ◽  
Malavika Raman
Keyword(s):  
Protein Aggregation ◽  
Mammalian Cells ◽  
Proteasome Inhibition ◽  
Adaptor Proteins ◽  
Ubiquitin Proteasome System ◽  
Aaa Atpase ◽  
Evolutionarily Conserved ◽  
Ubiquitin Proteasome ◽  
Aggresome Formation

AbstractThe recognition and disposal of misfolded proteins are essential for the maintenance of cellular homeostasis. Perturbations in the pathways that promote degradation of aberrant proteins contribute to a variety of protein aggregation disorders broadly termed proteinopathies. It is presently unclear how diverse disease-relevant aggregates are recognized and processed for degradation. The p97 AAA-ATPase in combination with a host of adaptor proteins functions to identify ubiquitylated proteins and target them for degradation by the ubiquitin-proteasome system or through autophagy. Mutations in p97 cause multi-system proteinopathies; however, the precise defects underlying these disorders are unclear given the large number of pathways that rely on p97 function. Here, we systematically investigate the role of p97 and its adaptors in the process of formation of aggresomes which are membrane-less structures containing ubiquitylated proteins that arise upon proteasome inhibition. We demonstrate that p97 mediates both aggresome formation and clearance in proteasome-inhibited cells. We identify a novel and specific role for the p97 adaptor UBXN1 in the process of aggresome formation. UBXN1 is recruited to ubiquitin-positive aggresomes and UBXN1 knockout cells are unable to form a single aggresome, and instead display dispersed ubiquitin aggregates. Furthermore, loss of p97-UBXN1 results in the increase in Huntingtin polyQ aggregates both in mammalian cells as well as in a C.elegans model of Huntington’s Disease. Together our work identifies evolutionarily conserved roles for p97 and its adaptor UBXN1 in the disposal of protein aggregates.

scholarly journals The p97-UBXN1 complex regulates aggresome formation

2021 ◽  
pp. jcs.254201
Author(s):  
Sirisha Mukkavalli ◽  
Jacob Aaron Klickstein ◽  
Betty Ortiz ◽  
Peter Juo ◽  
Malavika Raman
Keyword(s):  
Protein Aggregation ◽  
Mammalian Cells ◽  
Inclusion Bodies ◽  
Proteasome Inhibition ◽  
Adaptor Proteins ◽  
Cellular Homeostasis ◽  
Aaa Atpase ◽  
Evolutionarily Conserved ◽  
Aggresome Formation

The recognition and disposal of misfolded proteins is essential for the maintenance of cellular homeostasis. Perturbations in the pathways that promote degradation of aberrant proteins contribute to a variety of protein aggregation disorders broadly termed proteinopathies. The p97 AAA-ATPase in combination with adaptor proteins functions to identify ubiquitylated proteins and target them for degradation by the proteasome or autophagy. Mutations in p97 cause multi-system proteinopathies; however, the precise defects underlying these disorders are unclear. Here, we systematically investigate the role of p97 and its adaptors in the process of formation of aggresomes, membrane-less structures containing ubiquitylated proteins that arise upon proteasome inhibition. We demonstrate that p97 mediates aggresome formation and clearance and identify a novel role for the adaptor UBXN1 in the process of aggresome formation. UBXN1 is recruited to aggresomes and UBXN1 knockout cells are unable to form aggresomes. Loss of p97-UBXN1 results in increased Huntingtin polyQ inclusion bodies both in mammalian cells as well as in a C.elegans model of Huntington's Disease. Together our work identifies evolutionarily conserved roles for p97-UBXN1 in the disposal of protein aggregates.

Δ12-Prostaglandin J2 inhibits the ubiquitin hydrolase UCH-L1 and elicits ubiquitin–protein aggregation without proteasome inhibition

2004 ◽  
Vol 319 (4) ◽  
pp. 1171-1180 ◽  
Author(s):  
Zongmin Li ◽  
Francesco Melandri ◽  
Ingrid Berdo ◽  
Marlon Jansen ◽  
Lavonne Hunter ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Proteasome Inhibition ◽  
Prostaglandin J2

scholarly journals USP10 Is a Driver of Ubiquitinated Protein Aggregation and Aggresome Formation to Inhibit Apoptosis

iScience ◽  
2018 ◽  
Vol 9 ◽  
pp. 433-450 ◽  
Author(s):  
Masahiko Takahashi ◽  
Hiroki Kitaura ◽  
Akiyoshi Kakita ◽  
Taichi Kakihana ◽  
Yoshinori Katsuragi ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Ubiquitinated Protein ◽  
Aggresome Formation

scholarly journals The intrinsic chaperone network of Arabidopsis stem cells confers protection against proteotoxic stress

2021 ◽  
Author(s):  
Ernesto Llamas ◽  
Salvador Torres-Montilla ◽  
Hyun Ju Lee ◽  
María Victoria Barja ◽  
Elena Schlimgen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Protein Aggregation ◽  
Cell Function ◽  
Proteasome Inhibition ◽  
Stem Cell Maintenance ◽  
Proteotoxic Stress ◽  
Differentiated Cells ◽  
Plant Stem ◽  
Chaperone Network

AbstractThe biological purpose of plant stem cells is to maintain themselves while providing new pools of differentiated cells that form organs and rejuvenate or replace damaged tissues1-3. Protein homeostasis, or proteostasis, is required for cell function and viability4-7. However, the link between proteostasis and plant stem cell identity remains unknown. In contrast to their differentiated counterparts, we find that root stem cells can prevent the accumulation of aggregated proteins even under proteotoxic stress conditions such as heat stress or proteasome inhibition. Notably, root stem cells exhibit enhanced expression of distinct chaperones that maintain proteome integrity. Particularly, intrinsic high levels of the TRiC/CCT chaperonin determine stem cell maintenance and their remarkable ability to suppress protein aggregation. Overexpression of CCT8, a key activator of TRiC/CCT assembly8, is sufficient to ameliorate protein aggregation in differentiated cells and confer resistance to proteotoxic stress in plants. Taken together, our results indicate that enhanced proteostasis mechanisms in stem cells could be an important requirement for plants to persist under extreme environmental conditions and reach extreme long ages. Thus, proteostasis of stem cells could provide insights to design and breed plants tolerant to environmental challenges caused by the climate change.

scholarly journals Cell-state specific aggresome formation in fibroblasts is driven by stress-activated MAPK signaling

2021 ◽  
Author(s):  
Christopher S. Morrow ◽  
Zachary P. Arndt ◽  
Bo Peng ◽  
Eden Y. Zewdie ◽  
Bérénice A. Benayoun ◽  
...  
Keyword(s):  
Proteasome Inhibition ◽  
Fibroblast Cell ◽  
Mapk Signaling ◽  
Dermal Fibroblasts ◽  
Specific Response ◽  
Cell State ◽  
Distinct Cell ◽  
Aggresome Formation ◽  
Immortalized Cell ◽  
Universal Protein

The aggresome is a protein turnover system in which proteins are trafficked along microtubules to the centrosome for degradation. Despite extensive focus on aggresomes in immortalized cell lines, it remains unclear if the aggresome is conserved in all primary cells and all cell-states. Here we examined the aggresome in primary adult mouse dermal fibroblasts in four distinct cell-states. We found that in response to proteasome inhibition, quiescent and immortalized fibroblasts formed aggresomes whereas proliferating and senescent fibroblasts did not. Transcriptomic analysis of the fibroblast cell-state-specific response to proteasome inhibition revealed that stress-activated MAPK signaling was associated with aggresome formation. Supporting a functional role for stress-activated MAPK signaling in aggresome formation, inhibition of TAK1 and p38α/β MAPKs suppressed aggresome formation. Together, our data suggest that the aggresome is a non-universal protein degradation system that forms through stress-activated MAPK signaling which can be used cell-state specifically.

Improved Supra-Organization Is A Conformational And Functional Adaptation Of Respiratory Complexes

2020 ◽  
Author(s):  
Shivali Rawat ◽  
Suparna Ghosh ◽  
Debodyuti Mondal ◽  
Valpadashi Anusha ◽  
Swasti Raychaudhuri
Keyword(s):  
Protein Aggregation ◽  
Time Course ◽  
Protein Unfolding ◽  
Proteasome Inhibition ◽  
Cell Types ◽  
Relative Increase ◽  
Functional Adaptation ◽  
Respiratory Complexes ◽  
Multiple Protein ◽  
Multiple Cell

ABSTRACTMultiple surveillance mechanisms accelerate proteasome mediated degradation of misfolded proteins to prevent protein aggregation inside and outside mitochondria. But how cells safeguard mitochondrial function despite increased protein aggregation during proteasome inactivation? Here, using two-dimensional complexome profiling, we extensively characterize the dynamic states of respiratory complexes (RCs) in proteasome-inhibited cells. We report that RC-subunits are increasingly integrated into supra-organizations to optimize catalytic activity simultaneous to their aggregation inside mitochondria. Complex-II (CII) and CV are incorporated into oligomers. CI, CIII, and CIV subcomplexes are associated into holocomplexes followed by integration into supercomplexes. Time-course experiments reveal that the core (CI+CIII2) stoichiometry of supercomplex (I+III2+IV) is preserved during early-stress while CIV composition varies. Simultaneously, increased CI-activity suggests conformational optimization of supercomplexes for better function. Re-establishment of steady-state stoichiometry and relative increase in supercomplex-quantity consolidates functional adaptation during prolonged proteasome-inhibition. Together, we name this pre-emptive adaptive mechanism as ‘improved Supra-organization of Respiratory Complexes’ (iSRC). We find that iSRC is active in multiple protein-unfolding stresses, in multiple cell-types that differ in proteostatic and metabolic demands, and reversible upon stress-withdrawal.

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