In eukaryotic cells, an aggresome refers to an aggregation of

misfolded proteins Protein folding is the physical process by which a protein chain is translated to its native three-dimensional structure, typically a "folded" conformation by which the protein becomes biologically functional. Via an expeditious and reproduci ...

in the cell, formed when the

protein degradation Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Uncatalysed, the hydrolysis of peptide bonds is extremely slow, taking hundreds of years. Proteolysis is typically catalysed by cellular enzymes called protease ...

system of the cell is overwhelmed. Aggresome formation is a highly regulated process that possibly serves to organize misfolded proteins into a single location.

Biogenesis

Correct

folding Fold, folding or foldable may refer to: Arts, entertainment, and media * ''Fold'' (album), the debut release by Australian rock band Epicure * Fold (poker), in the game of poker, to discard one's hand and forfeit interest in the current pot *Abov ...

requires

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

s to assume one particular structure from a constellation of possible but incorrect conformations. The failure of

polypeptides Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. A p ...

to adopt their proper structure is a major threat to cell function and viability. Consequently, elaborate systems have evolved to protect cells from the deleterious effects of

. Cells mainly deploy three mechanisms to counteract misfolded proteins: up-regulating chaperones to assist protein refolding,

proteolytic Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Uncatalysed, the hydrolysis of peptide bonds is extremely slow, taking hundreds of years. Proteolysis is typically catalysed by cellular enzymes called protease ...

degradation of the misfolded/damaged proteins involving ubiquitin–proteasome and autophagy–lysosome systems, and formation of detergent-insoluble aggresomes by transporting the misfolded proteins along

microtubules Microtubules are polymers of tubulin that form part of the cytoskeleton and provide structure and shape to eukaryotic cells. Microtubules can be as long as 50 micrometres, as wide as 23 to 27 nm and have an inner diameter between 11 a ...

to a region near the

nucleus Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to: *Atomic nucleus, the very dense central region of an atom * Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA Nucl ...

. Intracellular deposition of misfolded protein aggregates into ubiquitin-rich cytoplasmic inclusions is linked to the

pathogenesis Pathogenesis is the process by which a disease or disorder develops. It can include factors which contribute not only to the onset of the disease or disorder, but also to its progression and maintenance. The word comes from Greek πάθος ''pat ...

of many diseases. Functional blockade of either degradative system leads to an enhanced aggresome formation. Why these aggregates form despite the existence of cellular machinery to recognize and degrade misfolded protein, and how they are delivered to cytoplasmic inclusions, are not known. Aggresome formation is accompanied by redistribution of the intermediate filament protein vimentin to form a cage surrounding a pericentriolar core of aggregated, ubiquitinated protein. Disruption of microtubules blocks the formation of aggresomes. Similarly, inhibition of proteasome function also prevents the degradation of unassembled presenilin-1 (PSE₁) molecules leading to their aggregation and deposition in aggresomes. Aggresome formation is a general response of cells which occurs when the capacity of the proteasome is exceeded by the production of aggregation-prone misfolded proteins. Typically, an aggresome forms in response to a cellular stress which generates a large amount of misfolded or partially

denatured protein In biochemistry, denaturation is a process in which proteins or nucleic acids lose the quaternary structure, tertiary structure, and secondary structure which is present in their native state, by application of some external stress or compound ...

hyperthermia Hyperthermia, also known simply as overheating, is a condition in which an individual's body temperature is elevated beyond normal due to failed thermoregulation. The person's body produces or absorbs more heat than it dissipates. When extreme ...

, overexpression of an insoluble or mutant protein, etc. The formation of the aggresome is largely believed to be a protective response, sequestering potentially cytotoxic aggregates and also acting as a staging center for eventual autophagic clearance from the cell. An aggresome forms around the

microtubule organizing center The microtubule-organizing center (MTOC) is a structure found in eukaryotic cells from which microtubules emerge. MTOCs have two main functions: the organization of eukaryotic flagella and cilia and the organization of the mitotic and meiotic spind ...

eukaryotic Eukaryotes () are organisms whose Cell (biology), cells have a cell nucleus, nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the ...

cells, adjacent to or enveloping the cell's

centrosome In cell biology, the centrosome (Latin centrum 'center' + Greek sōma 'body') (archaically cytocentre) is an organelle that serves as the main microtubule organizing center (MTOC) of the animal cell, as well as a regulator of cell-cycle prog ...

s. Polyubiquitination tags the protein for retrograde transport via HDAC6 binding and microtubule-based motor protein, dynein. Moreover, substrates can also be targeted to the aggresome by a ubiquitin-independent pathway mediated by the stress-induced co-chaperone

BAG3 BAG family molecular chaperone regulator 3 is a protein that in humans is encoded by the ''BAG3'' gene. BAG3 is involved in chaperone-assisted selective autophagy. Function BAG proteins compete with Hip-1 for binding to the Hsc70/Hsp70 ATPa ...

(Bcl-2-associated athanogene 3), which transfers misfolded protein substrates bound to

HSP70 The 70 kilodalton heat shock proteins (Hsp70s or DnaK) are a family of conserved ubiquitously expressed heat shock proteins. Proteins with similar structure exist in virtually all living organisms. Intracellularly localized Hsp70s are an import ...

(heat-shock protein 70) directly on to the microtubule motor dynein. The protein aggregate is then transported along the microtubule and unloaded via ATPase p97 forming the aggresome. Mediators such as p62 are believed to be involved in aggresome formation in sequestering omega-somes, which bind and increase the size of the aggresome. The aggresome is eventually targeted for autophagic clearance from the cell. Some pathological proteins, such as

alpha-synuclein Alpha-synuclein is a protein that, in humans, is encoded by the ''SNCA'' gene. Alpha-synuclein is a neuronal protein that regulates synaptic vesicle trafficking and subsequent neurotransmitter release. It is abundant in the brain, while smaller a ...

, cannot be degraded and cause the aggresomes to form inclusion bodies (in

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...

, Lewy bodies) which contribute to neuronal dysfunction and death.

Triggering aggresome formation

Abnormal polypeptides that escape proteasome-dependent degradation and aggregate in cytosol can be transported via microtubules to an aggresome, a recently discovered organelle where aggregated proteins are stored or degraded by autophagy. Synphilin 1, a protein implicated in Parkinson disease, was used as a model to study mechanisms of aggresome formation. When expressed in naïve HEK293 cells, synphilin 1 forms multiple small highly mobile aggregates. However, proteasome or Hsp90 inhibition rapidly triggered their translocation into the aggresome, and surprisingly, this response was independent on the expression level of synphilin 1. Therefore, aggresome formation, but not aggregation of synphilin 1, represents a special cellular response to a failure of the proteasome/chaperone machinery. Importantly, translocation to aggresomes required a special aggresome-targeting signal within the sequence of synphilin 1, an ankyrin-like repeat domain. On the other hand, formation of multiple small aggregates required an entirely different segment within synphilin 1, indicating that aggregation and aggresome formation determinants can be separated genetically. Furthermore, substitution of the ankyrin-like repeat in synphilin 1 with an aggresome-targeting signal from huntingtin was sufficient for aggresome formation upon inhibition of the proteasome. Analogously, attachment of the ankyrin-like repeat to a huntingtin fragment lacking its aggresome-targeting signal promoted its transport to aggresomes. These findings indicate the existence of transferable signals that target aggregation-prone polypeptides to aggresomes.

Human disease

Accumulation of misfolded proteins in proteinaceous inclusions is common to many age-related

neurodegenerative A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...

diseases, including

, Alzheimer's disease,

Huntington's disease Huntington's disease (HD), also known as Huntington's chorea, is a neurodegenerative disease that is mostly inherited. The earliest symptoms are often subtle problems with mood or mental abilities. A general lack of coordination and an uns ...

, and amyotrophic lateral sclerosis. In cultured cells, when the production of misfolded proteins exceeds the capacity of the chaperone refolding system and the ubiquitin-proteasome degradation pathway, misfolded proteins are actively transported to a cytoplasmic juxtanuclear structure called an aggresome. Whether aggresomes are benevolent or noxious is unknown, but they are of particular interest because of the appearance of similar inclusions in protein deposition diseases. Evidence shows that aggresomes serve a cytoprotective function and are associated with accelerated turnover of mutant proteins. Experiments show that mutant androgen receptor (AR), the protein responsible for X-linked spinobulbar muscular atrophy, forms insoluble aggregates and is toxic to cultured cells. Mutant AR was also found to form aggresomes in a process distinct from aggregation. Molecular and pharmacological interventions were used to disrupt aggresome formation, revealing their cytoprotective function. Aggresome-forming proteins were found to have an accelerated rate of turnover, and this turnover was slowed by inhibition of aggresome formation. Finally, it is shown that aggresome-forming proteins become membrane-bound and associate with lysosomal structures. Together, these findings suggest that aggresomes are cytoprotective, serving as cytoplasmic recruitment centers to facilitate degradation of toxic proteins.

Proteins implicated in aggresome formation

Histone deacetylase 6 is the protein that, in the deacetylase adaptor protein function, forms Lewy bodies (the regular wild-type protein localized to inclusion bodies). No mutation associated with disease has been linked to this protein. Parkin is the protein that, in the protein ligase function, forms Lewy bodies (the regular wild-type protein localized to inclusion bodies). Parkinson's disease has been linked to this protein when there is a protein. Ataxin-3 is the protein that, in the deubiquitinating enzyme function, forms SCA type-1 and 2 DRPLA intranuclear inclusions (the regular wild-type protein localized to inclusion bodies). SCA type-3 has been linked to this protein when there is a protein. Dynein motor complex is the protein that, in the retrograde microtubule motor function, forms an unknown protein (the regular wild-type protein localized to inclusion bodies). Motor neuron degeneration has been linked to this protein when there is a protein. Ubiquilin-1 is the protein that, in the protein turnover, intracellular trafficking function, forms Lewy bodies and neurofibrillary tangles (the regular wild-type protein localized to inclusion bodies). Alzheimer's disease (potential risk factor) has been linked to this protein when there is a protein.

Cystic fibrosis

Cystic fibrosis transmembrane conductance regulator Cystic fibrosis transmembrane conductance regulator (CFTR) is a membrane protein and anion channel in vertebrates that is encoded by the ''CFTR'' gene. Geneticist Lap-Chee Tsui and his team identified the CFTR gene in 1989 as the gene linked wi ...

(CFTR) is an inefficiently folded integral membrane protein that is degraded by the cytoplasmic ubiquitin-proteasome pathway. Overexpression or inhibition of proteasome activity in transfected human embryonic kidney cells or

Chinese hamster ovary cell Chinese hamster ovary (CHO) cells are an epithelial cell line derived from the ovary of the Chinese hamster, often used in biological and medical research and commercially in the production of recombinant therapeutic proteins. They have found wide ...

s leads to the accumulation of stable, high molecular weight, detergent-insoluble, multi-ubiquitinated forms of CFTR. Undergraded CFTR molecules accumulate at a distinct pericentriolar aggresome.

Role of the aggresome pathway in cancer

There is emerging evidence that inhibiting the aggresome pathway leads to accumulation of misfolded proteins and apoptosis in tumor cells through autophagy.

Biogenesis

Triggering aggresome formation

Human disease

Proteins implicated in aggresome formation

Cystic fibrosis

Role of the aggresome pathway in cancer

See also

References

Further reading