Aggresome
In eukaryotic cells, an aggresome refers to an aggregation of
Biogenesis
Correct
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
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
Typically, an aggresome forms in response to a cellular stress which generates a large amount of misfolded or partially
An aggresome forms around the
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
Proteins implicated in aggresome formation
Cystic fibrosis
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]
See also
References
Further reading
- Aggresomes: A Cellular Response to Misfolded Proteins
- Aggresomes protect cells by enhancing the degradation of toxic polyglutamine-containing protein
- Olzmann, JA; Li, L; Chin, LS (2008). "Aggresome formation and neurodegenerative diseases: therapeutic implications". Curr Med Chem. 15 (1): 47–60. PMID 18220762.
- Aggresome Formation and Neurodegenerative Diseases: Therapeutic Implications
- Role of the Aggresome Pathway in Cancer: Targeting Histone Deacetylase 6–Dependent Protein Degradation
- Zaarur, N; Meriin, AB; Gabai, VL; Sherman, MY (Oct 2008). "Triggering aggresome formation. Dissecting aggresome-targeting and aggregation signals in synphilin 1". J Biol Chem. 283 (41): 27575–84. PMID 18635553.
- Sitron, Cole S.; Hartl, F. Ulrich (2021-10-21). "A new way of D/Ealing with protein misfolding". Molecular Cell. 81 (20): 4114–4115. PMID 34686313.