JUNQ and IPOD
Segregation of toxic protein aggregates into JUNQ and IPOD inclusion bodies is a means by which mammalian cells can be rejuvenated through asymmetric division.
[7] Protein homeostasis (proteostasis),[8] results from the coordinated action of the different arms of the cellular quality control system: molecular chaperones, proteases and other regulatory factors.
Such management, by the quality control machinery, includes recognition of the misfolded protein by chaperones and E3 ligases, ubiquitination and degradation.
[citation needed] Proteostasis collapse, due to damage, stress, mutations, and aging, has been implicated as a basis for a large number of common human disorders, such as neurodegenerative diseases.
[2] The fate of misfolded proteins and the process leading to the formation of aggregate inclusions, were initially studied using biochemical methods (e.g. western blotting).
[citation needed] Deeper insights into the biological process of protein quality control and aggregation was made possible by a novel approach to looking at this problem, termed "Live Cell Imaging".
[10] Live cell imaging enables in vivo tracking of proteins in space and time, in their natural endogenous environment.
The folding reporter, a model protein for aggregation, was a Ubc9 (SUMO-conjugating enzyme) mutant (UBC9ts), harboring a missense mutation (Y68L) with a temperature- sensitive (ts) phenotype.
Strikingly, when the proteasome was impaired and clearance of the misfolded protein by degradation was blocked, two distinct cytosolic inclusions were observed to be formed.
Standard and conservative biochemical methods, such as cell fractionation and western blotting would not have revealed the partition into the two types of cytosolic aggregates.
[citation needed] The two detected inclusions were shown to be evolutionarily conserved quality control compartments, with different characteristics and distinct functions.
However, cellular increase of misfolded protein loads, due to various kinds of stresses (e.g. heat shock), may saturate and exhaust the quality control machinery.
[citation needed] The JUNQ is a non- membrane bound cellular site located in a margin of the nucleus, in close proximity to the endoplasmic reticulum.
It is becoming more evident that the cellular capacity to maintain proteostasis[8] declines with age,[9] thereby causing the late onset of neurodegenerative diseases.
The IPOD was shown[3] to be the sub-cellular site to which toxic amyloidogenic proteins are sequestered to, hereby serving as a protective quality control compartment.
