Autophagy is the name given to a complex, varied set of processes that tag and recycle broken or excess proteins and structures in the cell. The destination for materials to be recycled is the lysosome, a membrane-wrapped collection of enzymes capable of breaking down near all of the proteins and other molecules a cell is likely to encounter. How materials are selected and how exactly they make their way to the lysosome varies considerably. Alongside autophagy, the ubiquitin-proteasome system is another way for cells to identify problem proteins, such as those that misfold into toxic configurations, and then break them down into their component parts for reuse.
In short-lived species, improvement in autophagy or improvement in proteasomal degradation produces a slowing of aging. More effective cellular housekeeping implies a lower burden of damage inside cells, fewer downstream issues resulting from that damage, and thus better cell and tissue function. Today’s open access paper is one of many examples of researchers probing the complexities of cell maintenance, asking why some stem cell populations appear to undertake far too little proteasomal activity in order to clear out broken proteins. The authors found that these cells instead rely on a form of autophagy targeting the protein aggregates that can form as a result of misfolding.
All of these housekeeping processes decline in effectiveness with advancing age, and it is possible that ways to at least modestly slow the aging process can be found by improving cellular housekeeping in the stem cell populations responsible for supporting tissues by producing a consistent supply of new somatic cells. As noted here, the details and many possible targets for intervention are likely to be quite different from cell type to cell type. This encourages more holistic approaches such as partial reprogramming rather than going target by target in search of ways to manipulate the regulation of specific aspects of autophagy and proteasomal function.
Hematopoietic stem cells preferentially traffic misfolded proteins to aggresomes and depend on aggrephagy to maintain protein homeostasis
Maintenance of protein homeostasis (proteostasis) has emerged as fundamentally and preferentially important for stem cells. Proteostasis disruption impairs stem cell self-renewal, which contributes to poor ex vivo expansion and is associated with degenerative disorders, cancer predisposition syndromes, and age-related pathologies in vivo. To maintain proteostasis, cells employ a network of pathways to balance protein synthesis, folding, trafficking, and degradation. Despite being highly conserved, the proteostasis network can be specifically configured to support stem cell fitness and longevity.
Stem cells exhibit and depend on unusually low protein synthesis rates compared with restricted progenitors. Modest increases in protein synthesis disrupt stem cell proteostasis and impair self-renewal by increasing the biogenesis of misfolded proteins, but similar changes minimally impact progenitors. Similarly, activation of the unfolded protein response (UPR) has dichotomous effects in stem and progenitor cells. UPR activation safeguards the integrity of the stem cell pool by preferentially inducing apoptosis in stressed stem cells, whereas it typically promotes an adaptive response in progenitors.
In embryonic stem cells, high proteasome activity provides substantial proteostasis buffering capacity by degrading and preventing the accumulation of misfolded proteins. In contrast, proteasome activity is low within some stem cells such as neural stem cells and hematopoietic stem cells (HSCs). This raises a fundamental paradox: if somatic stem cells are highly dependent on proteostasis maintenance, why do they have such limited proteasome capacity to degrade misfolded proteins?
Here, we show that in contrast to most cells that primarily utilize the proteasome to degrade misfolded proteins, HSCs preferentially traffic misfolded proteins to aggresomes in a Bag3-dependent manner and depend on aggrephagy, a selective form of autophagy, to maintain proteostasis in vivo. When autophagy is disabled, HSCs compensate by increasing proteasome activity, but proteostasis is ultimately disrupted as protein aggregates accumulate and HSC function is impaired. Bag3-deficiency blunts aggresome formation in HSCs, resulting in protein aggregate accumulation, myeloid-biased differentiation, and diminished self-renewal activity. Furthermore, HSC aging is associated with a severe loss of aggresomes and reduced autophagic flux. Protein degradation pathways are thus specifically configured in young adult HSCs to preserve proteostasis and fitness but become dysregulated during aging.