Abstract
The C. elegans germline is pluripotent and mitotic, similar to self-renewing mammalian tissues. Apoptosis is triggered as part of the normal oogenesis program, and is increased in response to various stresses. Here, we examined the effect of endoplasmic reticulum (ER) stress on apoptosis in the C. elegans germline. We demonstrate that pharmacological or genetic induction of ER stress enhances germline apoptosis. This process is mediated by the ER stress response sensor IRE-1, but is independent of its canonical downstream target XBP-1. We further demonstrate that ire-1-dependent apoptosis in the germline requires both CEP-1/p53 and the same canonical apoptotic genes as DNA damage-induced germline apoptosis. Strikingly, we find that activation of ire-1, specifically in the ASI neurons, but not in germ cells, is sufficient to induce apoptosis in the germline. This implies that ER stress related germline apoptosis can be determined at the organism level, and is a result of active IRE-1 signaling in neurons. Altogether, our findings uncover ire-1 as a novel cell non-autonomous regulator of germ cell apoptosis, linking ER homeostasis in sensory neurons and germ cell fate.
Highlights
Apoptosis, known as programed cell death (PCD), is a highly conserved fundamental cellular process that provides a selfelimination mechanism for the removal of unwanted cells
We discovered that more germ cells undergo programmed cell death under stress conditions associated with the accumulation of misfolded proteins in the endoplasmic reticulum, a cellular organelle responsible for protein folding and trafficking
In response to endoplasmic reticulum (ER) stress, inositolrequiring protein-1 (IRE-1) activates the ER stressrelated transcription factor XBP-1, which induces the transcription of genes that help restore ER homeostasis [22,23,24]
Summary
Known as programed cell death (PCD), is a highly conserved fundamental cellular process that provides a selfelimination mechanism for the removal of unwanted cells. The physiological germ cell apoptosis pathway acts during oogenesis and is thought to act either as a part of a quality control process, preferentially removing unfit germ cells from the gonad, or as a resource re-allocation factor important for maintaining oocyte quality or as a gonad homeostatic pathway removing excess germ cells [6,11,12] Both somatic and germ cell apoptosis rely on the highly conserved core apoptotic machinery comprised of the Caspase-3 homolog ced-3, the Apaf-1 homolog ced-4 and the anti-apoptotic Bcl-2 homolog ced-9 [6,13,14,15,16]
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