Germline stem cell arrest inhibits the collapse of somatic proteostasis early inCaenorhabditis elegansadulthood

Abstract

SummaryAll cells rely on highly conserved protein folding and clearance pathways to detect and resolve protein damage and to maintain protein homeostasis (proteostasis). Because age is associated with an imbalance in proteostasis, there is a need to understand how protein folding is regulated in a multicellular organism that undergoes aging. We have observed that the ability of Caenorhabditis elegans to maintain proteostasis declines sharply following the onset of oocyte biomass production, suggesting that a restricted protein folding capacity may be linked to the onset of reproduction. To test this hypothesis, we monitored the effects of different sterile mutations on the maintenance of proteostasis in the soma of C. elegans. We found that germline stem cell (GSC) arrest rescued protein quality control, resulting in maintenance of robust proteostasis in different somatic tissues of adult animals. We further demonstrated that GSC-dependent modulation of proteostasis requires several different signaling pathways, including hsf-1 and daf-16/kri-1/tcer-1, daf-12, daf-9, daf-36, nhr-80, and pha-4 that differentially modulate somatic quality control functions, such that each signaling pathway affects different aspects of proteostasis and cannot functionally complement the other pathways. We propose that the effect of GSCs on the collapse of proteostasis at the transition to adulthood is due to a switch mechanism that links GSC status with maintenance of somatic proteostasis via regulation of the expression and function of different quality control machineries and cellular stress responses that progressively lead to a decline in the maintenance of proteostasis in adulthood, thereby linking reproduction to the maintenance of the soma.

The role of protein clearance mechanisms in organismal ageing and age-related diseases

“…Hypothetically, the need for repairing and preventing damage to the germline dominates resource allocation strategies, while the somatic tissues age and deteriorate 73 . In support of such theory, modulations of reproduction that eliminate germ cells in C. elegans and D. melanogaster extend lifespan 171 , a phenotype that may be caused by heightened proteome stability within the post-mitotic soma 54,172 . Inhibiting germline proliferation induces an increased in proteasome activity and RPN6 levels in the somatic tissues and protects from polyQ-dependent aggregation 54,172 .…”

“…In support of such theory, modulations of reproduction that eliminate germ cells in C. elegans and D. melanogaster extend lifespan 171 , a phenotype that may be caused by heightened proteome stability within the post-mitotic soma 54,172 . Inhibiting germline proliferation induces an increased in proteasome activity and RPN6 levels in the somatic tissues and protects from polyQ-dependent aggregation 54,172 . Similar to (a) Proteasome activity declines with ageing as a consequence of a reduction in the expression of proteasomal subunits, alteration or replacement of several proteasomal subunits, disassembly of the proteasome or inactivation of the proteasome through direct interaction with age-induced protein aggregates.…”

Protein Quality Control in Health and Disease

“…The expression of a constitutively active isoform of the transcription factor XBP (XBPs) in neurons activates the UPR ER in distal tissues (Taylor and Dillin 2013). Further evidence supporting the roles of neurons in the regulation of UPR ER was recently provided by the report that the overactivation of IRE1 in ASI neurons promotes apoptosis of the worm's germ cells (LeviFerber et al 2014), cells whose ablation confers proteostasis in muscle cells (Shemesh et al 2013). Similarly, UPR mt is activated in the nematode intestine by the inhibition of the electron transport chain in neurons (Durieux et al 2011).…”

Using <em>Caenorhabditis elegans</em> as a Model System to Study Protein Homeostasis in a Multicellular Organism

“…We avoid using prolonged stress treatments because the time resolution of a 15 hr survival assay can be limiting when monitoring changes in HS survival. For example, upon transition to adulthood, there is a fast change in the ability of C. elegans to activate the HS response, an event that is shorter than the typical kinetic thermo-resistance assay 52 . Moreover, by monitoring survival rates when ~70% of wild type animals survive under control conditions, we can easily detect modifiers that enhance or reduce stress survival by monitoring only a single time point, simplifying the assay.…”