Gonadotropin-releasing hormone-like receptor 2 inversely regulates somatic proteostasis and reproduction in Caenorhabditis elegans

Abstract

The quality control machinery regulates the cellular proteome to ensure proper protein homeostasis (proteostasis). In Caenorhabditis elegans, quality control networks are downregulated cell-nonautonomously by the gonadal longevity pathway or metabolic signaling at the onset of reproduction. However, how signals are mediated between the gonad and the somatic tissues is not known. Gonadotropin-releasing hormone (GnRH)-like signaling functions in the interplay between development and reproduction and have conserved roles in regulating reproduction, metabolism, and stress. We, therefore, asked whether GnRH-like signaling is involved in proteostasis collapse at the onset of reproduction. Here, we examine whether C. elegans orthologues of GnRH receptors modulate heat shock survival. We find that gnrr-2 is required for proteostasis remodeling in different somatic tissues during the transition to adulthood. We show that gnrr-2 likely functions in neurons downstream of the gonad in the gonadal-longevity pathway and modulate the somatic regulation of transcription factors HSF-1, DAF-16, and PQM-1. In parallel, gnrr-2 modulates egg-laying rates, vitellogenin production, and thus reproductive capacity. Taken together, our data suggest that gnrr-2 plays a GnRH-associated role, mediating the cross-talk between the reproduction system and the soma in the decision to commit to reproduction.

Evolutionary conserved peptide and glycoprotein hormone-like neuroendocrine systems in C. elegans

“…Besides GNRR-1, the C. elegans genome encodes seven paralogous AKH/GnRH-like receptors, named GNRR-2 to GNRR-8 ( Frooninckx et al, 2012 ; Meethal et al, 2006 ; Van der Auwera et al, 2020 ). To date, only GNRR-2, GNRR-3, GNRR-6, and GNRR-8/DAF-38 have been functionally characterized ( Kishner et al, 2022 ; Park et al, 2012 ; Peng et al, 2023 ; Van der Auwera et al, 2020 ). GNRR-2 is involved in the modulation of the heat shock response (HSR), protein homeostasis (proteostasis), and organismal commitment to reproduction ( Kishner et al, 2022 ).…”

“…To date, only GNRR-2, GNRR-3, GNRR-6, and GNRR-8/DAF-38 have been functionally characterized ( Kishner et al, 2022 ; Park et al, 2012 ; Peng et al, 2023 ; Van der Auwera et al, 2020 ). GNRR-2 is involved in the modulation of the heat shock response (HSR), protein homeostasis (proteostasis), and organismal commitment to reproduction ( Kishner et al, 2022 ). These effects were found to be regulated at the onset of adulthood wherein resource allocation is required and reproduction versus fitness trade-offs are made ( Kishner et al, 2022 ).…”

“…GNRR-2 is involved in the modulation of the heat shock response (HSR), protein homeostasis (proteostasis), and organismal commitment to reproduction ( Kishner et al, 2022 ). These effects were found to be regulated at the onset of adulthood wherein resource allocation is required and reproduction versus fitness trade-offs are made ( Kishner et al, 2022 ). It remains to be determined whether GNRR-2 is activated by a GnRH/AKH-like peptide as no ligands of GNRR-2 have been reported to date ( Kishner et al, 2022 ; Van der Auwera et al, 2020 ).…”

“…These effects were found to be regulated at the onset of adulthood wherein resource allocation is required and reproduction versus fitness trade-offs are made ( Kishner et al, 2022 ). It remains to be determined whether GNRR-2 is activated by a GnRH/AKH-like peptide as no ligands of GNRR-2 have been reported to date ( Kishner et al, 2022 ; Van der Auwera et al, 2020 ). While GNRR-8/DAF-38 has also been linked to reproduction (reduced brood size in gnrr-8 mutants), it seems to play more central roles in mediating ascaroside pheromone signaling ( Park et al, 2012 ; Peng et al, 2023 ).…”

Regulation of the proteostasis network by the neuronal system

“…Signals that originate from the reproductive system govern both acute proteotoxicity inflicted by heat stress (Shemesh et al, 2013;Labbadia and Morimoto, 2015) and chronic proteostasis impairment by the expression of neurodegenerationlinked proteins (Moll et al, 2018). Interestingly, gnrr-2 which codes a neuronal GPCR, is a proteostasis regulator that functions downstream of signaling that originates from the reproductive system, and regulates the transcription factors DAF-16/FOXO, HSF-1 and PQM-1 (Kishner et al, 2022). In fact, signals that emanate from the reproductive system as a result of DNA damage, integrate with signals that stem from the intestine, an emerging proteostasis-coordinating tissue (Hodge et al, 2022), due to exposure to pathogens to enhance UPS activity and promote proteostasis across the organism (Ermolaeva et al, 2013).…”