Regeneration in starved planarians depends on TRiC/CCT subunits modulating the unfolded protein response

Abstract

Planarians are able to stand long periods of starvation by maintaining adult stem cell pools and regenerative capacity. The molecular pathways that are needed for the maintenance of regeneration during starvation are not known. Here, we show that down‐regulation of chaperonin TRiC/CCT subunits abrogates the regeneration capacity of planarians during starvation, but TRiC/CCT subunits are dispensable for regeneration in fed planarians. Under starvation, they are required to maintain mitotic fidelity and for blastema formation. We show that TRiC subunits modulate the unfolded protein response (UPR) and are required to maintain ATP levels in starved planarians. Regenerative defects in starved CCT‐depleted planarians can be rescued by either chemical induction of mild endoplasmic reticulum stress, which leads to induction of the UPR, or by the supplementation of fatty acids. Together, these results indicate that CCT‐dependent UPR induction promotes regeneration of planarians under food restriction.

PI(18:1/18:1) is a SCD1-derived lipokine that limits stress signaling

“…However, starvation markedly reduced the proportion of PI(18:1/18:1) in planarians with diminished ER stress tolerance (Fig. 9g ) when either Smed - xbp1 / Smed - atf6 or Smed - cct3A was silenced 77 . To explore the impact of Smed - cct3A on stress signaling, we analyzed the published cct3A RNAi transcriptome of starved planarians 77 .…”

“…9g ) when either Smed - xbp1 / Smed - atf6 or Smed - cct3A was silenced 77 . To explore the impact of Smed - cct3A on stress signaling, we analyzed the published cct3A RNAi transcriptome of starved planarians 77 . The central autophagosomal mRNA lc3 (PlanMine id: dd_Smed_v6_2838_0_1) was substantially upregulated by cct3A RNAi (Fig.…”

“…Double-stranded RNA (dsRNA) was synthesized by in vitro transcription with a MEGAscript RNAi kit (Ambion), and dsRNA was injected into the planarian. Following oligonucleotides were used to generate templates for dsRNA production: (1) Smed-xbp1-F: 5ʹ-TAGGTGGGAATGGTATGGGAAA-3ʹ, Smed-xbp1-R: 5ʹ-CACAACCAAACTCTGACATTTCG-3ʹ; (2) Smed-atf6-F: 5ʹ-AAGCCAGTTGTTAAGCCAGAAA-3ʹ, Smed-atf6-R: 5ʹ-CCATGATAACCGGGAAATGAAGA-3ʹ; (3) Smed-cct3A-F: 5ʹ-CGTCGTTTTGAGTGGAGTTTTG-3ʹ, Smed-cct3A-R: 5ʹ-TTGATATTGCCATCTCCAATGC-3ʹ 77 . Control animals were injected with gfp dsRNA (GenBank: M62653.1), a sequence not present in the planarian genome.…”

“…Planarians were amputated anterior and posterior to the pharynx on day 8 after the first injection and only trunks were processed for lipid extraction. RNA-Seq data from a previous study 77 has been deposited in Expression Omnibus (GEO) with the accession number GSE134013. Significance was determined by q -value (false discovery rate (FDR)) < 0.1 for pairwise comparisons.…”

Local problems need global solutions: The metabolic needs of regenerating organisms

“…Starving organisms lower their metabolic rates and many enter dormancy‐like states to endure long periods of food deprivation. Nevertheless, some species maintain their regenerative capacity despite none or insufficient food consumption 142,143 . It appears that fasting or fasting mimicking diets can sensitise metabolic pathways 144 and promote regeneration 145 .…”