Aggresome

Last updated August 14, 2023

In eukaryotic cells, an aggresome refers to an aggregation of misfolded proteins in the cell, formed when the protein degradation system of the cell is overwhelmed. Aggresome formation is a highly regulated process that possibly serves to organize misfolded proteins into a single location.^[1]

Biogenesis

Correct folding requires proteins to assume one particular structure from a constellation of possible but incorrect conformations. The failure of polypeptides 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 misfolded proteins.

Upon synthesis, proteins are in their linear and non-functional form, called a nascent protein. They must undergo co-translational folding as quickly as possible in order to become a functional, three-dimensional structure. Normally folded proteins are referred to as being in their native structure. In this state, they have undergone a hydrophobic collapse process, indicated by outward-facing hydrophilic components and inward-facing hydrophobic components.

The solubility of proteins is an important biochemical aspect of protein folding as it has been shown to affect the formation of protein aggregates. Contrary to native structures, a misfolded protein will often have outward-facing hydrophobic regions which acts as an attractant to other insoluble proteins. There are some chaperones which identify aggregates by recognizing their hydrophobic region. These chaperone may work as solubilizers.

Cells mainly deploy three mechanisms to counteract misfolded proteins: up-regulating chaperones to assist protein refolding, proteolytic 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 to a region near the nucleus. Intracellular deposition of misfolded protein aggregates into ubiquitin-rich cytoplasmic inclusions is linked to the pathogenesis 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: hyperthermia, 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 in eukaryotic cells, adjacent to or enveloping the cell's centrosomes. Polyubiquitination tags the protein for retrograde transport via HDAC6 binding and microtubule-based motor protein, dynein.^[2] Moreover, substrates can also be targeted to the aggresome by a ubiquitin-independent pathway mediated by the stress-induced co-chaperone BAG3 (Bcl-2-associated athanogene 3), which transfers misfolded protein substrates bound to HSP70 (heat-shock protein 70) directly on to the microtubule motor dynein.^[3] 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, cannot be degraded and cause the aggresomes to form inclusion bodies (in Parkinson's disease, Lewy bodies) which contribute to neuronal dysfunction and death.^[4]

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 diseases, including Parkinson's disease, Alzheimer's disease, Huntington's disease, 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 (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 cells 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.^[5]

Related Research Articles

Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases.

Lewy bodies are the inclusion bodies – abnormal aggregations of protein – that develop inside nerve cells affected by Parkinson's disease (PD), the Lewy body dementias, and some other disorders. They are also seen in cases of multiple system atrophy, particularly the parkinsonian variant (MSA-P).

Autophagy is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent regulated mechanism. It allows the orderly degradation and recycling of cellular components. Although initially characterized as a primordial degradation pathway induced to protect against starvation, it has become increasingly clear that autophagy also plays a major role in the homeostasis of non-starved cells. Defects in autophagy have been linked to various human diseases, including neurodegeneration and cancer, and interest in modulating autophagy as a potential treatment for these diseases has grown rapidly.

The heat shock response (HSR) is a cell stress response that increases the number of molecular chaperones to combat the negative effects on proteins caused by stressors such as increased temperatures, oxidative stress, and heavy metals. In a normal cell, proteostasis must be maintained because proteins are the main functional units of the cell. Many proteins take on a defined configuration in a process known as protein folding in order to perform their biological functions. If these structures are altered, critical processes could be affected, leading to cell damage or death. The heat shock response can be employed under stress to induce the expression of heat shock proteins (HSP), many of which are molecular chaperones, that help prevent or reverse protein misfolding and provide an environment for proper folding.

Inclusion bodies are aggregates of specific types of protein found in neurons, a number of tissue cells including red blood cells, bacteria, viruses, and plants. Inclusion bodies of aggregations of multiple proteins are also found in muscle cells affected by inclusion body myositis and hereditary inclusion body myopathy.

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 lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple system atrophy, and prion diseases. Neurodegeneration can be found in the brain at many different levels of neuronal circuitry, ranging from molecular to systemic. Because there is no known way to reverse the progressive degeneration of neurons, these diseases are considered to be incurable; however research has shown that the two major contributing factors to neurodegeneration are oxidative stress and inflammation. Biomedical research has revealed many similarities between these diseases at the subcellular level, including atypical protein assemblies and induced cell death. These similarities suggest that therapeutic advances against one neurodegenerative disease might ameliorate other diseases as well.

A viroplasm, sometimes called "virus factory" or "virus inclusion", is an inclusion body in a cell where viral replication and assembly occurs. They may be thought of as viral factories in the cell. There are many viroplasms in one infected cell, where they appear dense to electron microscopy. Very little is understood about the mechanism of viroplasm formation.

Endoplasmic-reticulum-associated protein degradation (ERAD) designates a cellular pathway which targets misfolded proteins of the endoplasmic reticulum for ubiquitination and subsequent degradation by a protein-degrading complex, called the proteasome.

Ubiquitin-activating enzymes, also known as E1 enzymes, catalyze the first step in the ubiquitination reaction, which can target a protein for degradation via a proteasome. This covalent bond of ubiquitin or ubiquitin-like proteins to targeted proteins is a major mechanism for regulating protein function in eukaryotic organisms. Many processes such as cell division, immune responses and embryonic development are also regulated by post-translational modification by ubiquitin and ubiquitin-like proteins.

The unfolded protein response (UPR) is a cellular stress response related to the endoplasmic reticulum (ER) stress. It has been found to be conserved between mammalian species, as well as yeast and worm organisms.

<span class="mw-page-title-main">Valosin-containing protein</span> Protein-coding gene in the species Homo sapiens

Valosin-containing protein (VCP) or transitional endoplasmic reticulum ATPase also known as p97 in mammals and CDC48 in S. cerevisiae, is an enzyme that in humans is encoded by the VCP gene. The TER ATPase is an ATPase enzyme present in all eukaryotes and archaebacteria. Its main function is to segregate protein molecules from large cellular structures such as protein assemblies, organelle membranes and chromatin, and thus facilitate the degradation of released polypeptides by the multi-subunit protease proteasome.

26S proteasome non-ATPase regulatory subunit 2, also as known as 26S Proteasome Regulatory Subunit Rpn1, is an enzyme that in humans is encoded by the PSMD2 gene.

E3 ubiquitin-protein ligase SMURF1 is an enzyme that in humans is encoded by the SMURF1 gene. The SMURF1 Gene encodes a protein with a size of 757 amino acids and the molecular mass of this protein is 86114 Da.

Autophagy related 16 like 1 is a protein that in humans is encoded by the ATG16L1 gene. This protein is characterized as a subunit of the autophagy-related ATG12-ATG5/ATG16 complex and is essentially important for the LC3 (ATG8) lipidation and autophagosome formation. This complex localizes to the membrane and is released just before or after autophagosome completion.

In molecular biology, protein aggregation is a phenomenon in which intrinsically-disordered or mis-folded proteins aggregate either intra- or extracellularly. Protein aggregates have been implicated in a wide variety of diseases known as amyloidoses, including ALS, Alzheimer's, Parkinson's and prion disease.

Proteostasis is the dynamic regulation of a balanced, functional proteome. The proteostasis network includes competing and integrated biological pathways within cells that control the biogenesis, folding, trafficking, and degradation of proteins present within and outside the cell. Loss of proteostasis is central to understanding the cause of diseases associated with excessive protein misfolding and degradation leading to loss-of-function phenotypes, as well as aggregation-associated degenerative disorders. Therapeutic restoration of proteostasis may treat or resolve these pathologies. Cellular proteostasis is key to ensuring successful development, healthy aging, resistance to environmental stresses, and to minimize homeostatic perturbations from pathogens such as viruses. Cellular mechanisms for maintaining proteostasis include regulated protein translation, chaperone assisted protein folding, and protein degradation pathways. Adjusting each of these mechanisms based on the need for specific proteins is essential to maintain all cellular functions relying on a correctly folded proteome.

<span class="mw-page-title-main">JUNQ and IPOD</span>

JUNQ and IPOD are types of cytosolic protein inclusion bodies in eukaryotes.

Chaperone-assisted selective autophagy is a cellular process for the selective, ubiquitin-dependent degradation of chaperone-bound proteins in lysosomes.

The pathophysiology of Parkinson's disease is death of dopaminergic neurons as a result of changes in biological activity in the brain with respect to Parkinson's disease (PD). There are several proposed mechanisms for neuronal death in PD; however, not all of them are well understood. Five proposed major mechanisms for neuronal death in Parkinson's Disease include protein aggregation in Lewy bodies, disruption of autophagy, changes in cell metabolism or mitochondrial function, neuroinflammation, and blood–brain barrier (BBB) breakdown resulting in vascular leakiness.

Animal models of Parkinson's disease are essential in the research field and widely used to study Parkinson's disease. Parkinson's disease is a neurodegenerative disorder, characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The loss of the dopamine neurons in the brain, results in motor dysfunction, ultimately causing the four cardinal symptoms of PD: tremor, rigidity, postural instability, and bradykinesia. It is the second most prevalent neurodegenerative disease, following Alzheimer's disease. It is estimated that nearly one million people could be living with PD in the United States.

References

↑ Corboy MJ, Thomas PJ, Wigley WC (2005). "Aggresome formation". Ubiquitin-Proteasome Protocols. Methods Mol. Biol. Vol. 301. pp. 305–27. doi:10.1385/1-59259-895-1:305. ISBN 978-1-59259-895-3. PMID 15917642.
↑ Johnston, J.A.; Ward, C.L.; Kopito, R.R. (1998). "Aggresomes: A Cellular Response to Misfolded Proteins". J. Cell Biol. 143 (7): 1883–1898. doi:10.1083/jcb.143.7.1883. PMC 2175217 . PMID 9864362.
↑ Gamerdinger, M; Kaya, AM; Wolfrum, U; Clement, AM; Behl, C (2011). "BAG3 mediates chaperone‐based aggresome‐targeting and selective autophagy of misfolded proteins". EMBO Rep. 12 (2): 149–56. doi:10.1038/embor.2010.203. PMC 3049430 . PMID 21252941.
↑ Finger, pp. 43–50
↑ Rodriguez-Gonzalez, A (April 2008). "Role of the aggresome pathway in cancer: targeting histone deacetylase 6-dependent protein degradation". Cancer Res. 15 (68): 2557–60. doi: 10.1158/0008-5472.CAN-07-5989 . PMID 18413721.