On Proteostasis and the Endoplasmic Reticulum

Proteostasis is a shorthand term used to mean that the balance of proteins in cells remains steady and correct over time: proteins are produced and destroyed at more or less the same pace, relative levels of different proteins in different places in cells remain the same, levels of damaged proteins are low and consistent, and so forth. There are always ongoing variations in the amounts of some proteins in some places, as this is how the machinery of metabolism works, but overall you'd expect to see much the same thing tomorrow as you do today. Aging disrupts proteostasis, however. It changes the picture of what is going on inside cells through both an increased level of damaged proteins and altered rates of production of many proteins: cellular machinery reacts to local damage directly and remote damage through signaling networks and altered levels of circulating proteins outside cells.

By way of following on from yesterday's post on proteostasis in naked mole rats, a species that shows only comparatively small changes in the machinery of metabolism over much of the course of its life span, here is a paper on the role of the endoplasmic reticulum in proteostasis. Much of it is in the context of genetic conditions unrelated to aging, and their effects on proteostasis, but it is still relevant and interesting material:

The endoplasmic reticulum (ER) is an intracellular compartment dedicated to the synthesis and maturation of secretory and membrane proteins, totalling about 30% of the total eukaryotic cells proteome. The capacity to produce correctly folded polypeptides and to transport them to their correct intra- or extracellular destinations relies on proteostasis networks that regulate and balance the activity of protein folding, quality control, transport and degradation machineries. Nutrient and environmental changes, pathogen infection, aging, and, more relevant for the topics discussed in this review, mutations that impair attainment of the correct 3D structure of nascent polypeptide chains may compromise the activity of the proteostasis networks with devastating consequences on cells, organs and organisms' homeostasis.

Production and maintenance of a functional proteome is crucial for cells, tissues and organisms viability. Highly efficient folding, quality control and transport machineries located in specific intracellular compartments such as the ER convert the genetic information stored into the cell nuclei into functional proteins and protein complexes that fulfil the wide array of functions required for life. Paradoxically, mutations that do not affect the function of a given polypeptide may result in debilitating and life threatening diseases if they introduce small structural defects. In fact, the quality control devices that prevent exit of aberrant polypeptides from the biosynthetic compartment and insure their clearance from cells are alerted by non native features such as exposure at the polypeptide surface of hydrophobic patches, unpaired cysteine residues or otherwise unstructured determinants, independent of the capacity of the mutant polypeptide to fulfil its biological activity.

This "quality control paradox" highlights the importance of basic research in cell biology aiming at understanding the molecular basis of retention- and degradation-based mechanisms operating in our cells. Characterisation of these processes at the molecular level is required to develop therapeutic interventions that promote selective export of functional mutant proteins inappropriately segregated for architectural biases or to sustain "unfolded protein responses" that must intervene when misfolded polypeptides start to accumulate in or outside cells. This becomes even more important for aging-related diseases such as many neurodegenerative disorders, which result from gradual impairment of the proteostasis network, as the increased life expectancy is a fact in our society, and the number of patients will ineluctably raise.

Link: http://www.smw.ch/content/smw-2014-14001/


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