Protecting the future: balancing proteostasis for reproduction

Abstract

The proteostasis network (PN) regulates protein synthesis, folding, and degradation and is critical for the health and function of all cells. The PN has been extensively studied in the context of aging and age-related diseases, and loss of proteostasis is regarded as a major contributor to many age-associated disorders. In contrast to somatic tissues, an important feature of germ cells is their ability to maintain a healthy proteome across generations. Accumulating evidence has now revealed multiple layers of PN regulation that support germ cell function, determine reproductive capacity during aging, and prioritize reproduction at the expense of somatic health. Here, we review recent insights into these different modes of regulation and their implications for reproductive and somatic aging.

Keywords: aging; oocyte; proteostasis; reproduction; stress response.

Figure 1.. Mechanisms that promote proteostasis in germ cells

The different steps of male (left) and female (right) gametogenesis, and subsequent fertilization, are represented. Several mechanisms to maintain proteostasis during reproduction have been identified and can be broadly classified as (i) specific proteostasis network (PN) programs including elevated expression of ubiquitous components and expression of specialized components, to maintain the proteome of germ cells and prevent protein damage, (ii) the elimination of damaged cells via apoptosis which can be triggered by activation of cell stress responses, and (iii) the removal of misfolded and aggregated proteins by degradations pathways before or following fertilization to reset proteostasis.

Figure 2.. Age-dependent loss of proteostasis in oocytes

Loss of proteostasis during aging in arrested oocytes contribute to the age-related decline in oocyte quality. In young oocytes, a functional proteostasis network (PN) and antioxidant mechanisms limit protein misfolding and aggregation, thereby maintaining a healthy proteome that supports oocyte meiosis and function. During aging, a functional decline in molecular chaperones, degradation pathways, and antioxidant responses lead to the accumulation of misfolded and aggregated proteins, and results in a state of chronic proteome imbalance. This compromises the ability to successfully complete meiosis and contributes to the decline of oocyte quality.

Figure 3.. Regulation of somatic proteostasis by the reproductive system in C. elegans

Studies in C. elegans have revealed multiple modes of regulation of somatic proteostasis by the reproductive system. During normal development, signals from germline stem cells (GSC) repress the heat shock response (HSR) at reproductive maturity dependent upon reduced expression of the demethylase JMJD-3.1. In addition, different perturbations of the germline activate proteostasis-promoting pathways in somatic tissues. Mutations that induce GSC arrest enhance the heat-shock response, the autophagy-lysosome pathway, and the ubiquitin-proteasome system (UPS). DNA damage to germ cells activates an MPK-1-dependent innate immune response that elevates the activity of the UPS in somatic tissues. Damage to the vitelline layer of fertilized egg in the uterus activates a DAF-16/FOXO response specifically in vulva tissues and restores the HSR in somatic tissues of adult animals.