Abstract
The appearance of protein aggregates is a hallmark of several pathologies including many neurodegenerative diseases. Mounting evidence suggests that the accumulation of misfolded proteins into inclusions is a secondary line of defense when the extent of protein misfolding exceeds the capacity of the Protein Quality Control System, which mediates refolding or degradation of misfolded species. Such exhaustion can occur during severe proteotoxic stress, the excessive occurrence of aggregation prone protein species, e.g., amyloids, or during ageing. However, the machinery that mediates recognition, recruitment and deposition of different types of misfolded proteins into specific deposition sites is only poorly understood. Since emerging principles of aggregate deposition appear evolutionarily conserved, yeast represents a powerful model to study basic mechanisms of recognition of different types of misfolded proteins, their recruitment to the respective deposition site and the molecular organization at the corresponding site. Yeast possesses at least three different aggregate deposition sites, one of which is a major deposition site for amyloid aggregates termed Insoluble PrOtein Deposit (IPOD). Due to the link between neurodegenerative disease and accumulation of amyloid aggregates, the IPOD is of particular interest when we aim to identify the molecular mechanisms that cells have evolved to counteract toxicity associated with the occurrence of amyloid aggregates. Here, we will review what is known about IPOD composition and the mechanisms of recognition and recruitment of amyloid aggregates to this site in yeast. Finally, we will briefly discuss the possible physiological role of aggregate deposition at the IPOD.
Highlights
The Protein Quality Control System, comprising molecular chaperones and proteolytic machineries, ensures that proteins reach and maintain their native state
A contribution of autophagy on turnover of prion domain of Sup35 and GFP (PrD-GFP) residing at the Insoluble PrOtein Deposit (IPOD) could not be excluded, there was no direct evidence found for this (Kumar et al, 2016)
This is purely speculative, interfering with Sec21 function may potentially affect Atg9 vesicle biogenesis at the Golgi. These data indicate that vesicle-based transport along actin cables plays an important role in recruitment of amyloids to the IPOD. This rather new concept of aggregates hitchhiking vesicular transport routes was proposed by Nystroem and co-workers when they observed that deletion or overexpression of components of the vacuole inheritance machinery or endocytic vesicles, among them Vps1 and the myosin dependent adaptor protein Vac17, impaired or enhanced, respectively, recruitment of heat induced and Hsp104 bound aggregates to a perivacuolar inclusion site reminiscent of the IPOD (Hill et al, 2016)
Summary
The Protein Quality Control System, comprising molecular chaperones and proteolytic machineries, ensures that proteins reach and maintain their native state. It recognizes misfolded species and either reverts them to the native state or eliminates them (Bukau et al, 2006; Hartl and Hayer-Hartl, 2009). Insoluble fibrous aggregates with a very high content of β-strands being oriented perpendicularly to the fibril axis. Their occurrence is a hallmark of several fatal neurodegenerative diseases (Knowles et al, 2014). It is currently still under debate why amyloid aggregates can become detrimental to the cell, but it
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