Decision letter | Lipid-mediated regulation of SKN-1/Nrf in response to germ cell absence

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Lipid-mediated regulation of SKN-1/Nrf in response to germ cell absence

Decision letter

Affiliation details

Joslin Diabetes Center, United States; Harvard Medical School, United States; Boston University, United States
Kang Shen, Reviewing editor, Howard Hughes Medical Institute, Stanford University, United States

In the interests of transparency, eLife includes the editorial decision letter and accompanying author responses. A lightly edited version of the letter sent to the authors after peer review is shown, indicating the most substantive concerns; minor comments are not usually included.

Thank you for sending your work entitled “Lipid-mediated regulation of SKN-1/Nrf in response to germ cell ablation” for consideration at eLife. Your article has been favorably evaluated by K VijayRaghavan (Senior editor), a Reviewing editor, and two reviewers.

The reviewers found this manuscript interesting and potentially suitable for publication in eLife. For instance, one reviewer wrote: “This is an excellent, well written, and data-rich manuscript. Along the way, the authors correct findings published in several high profile papers by others and provide a refreshing interpretation of the nature of the lipid accumulation in glp-1 mutants and the role of SKN-1 in response to this lipid overload. As such, it is a dramatic advance for a field that has generally ignored the role of intestinal yolk and simply interpreted all lipids in the intestine as the equivalent of adipose-like storage depots. The authors also do a thorough job of incorporating a variety of mutants that have been previously implicated in glp-1 lifespan extension in the context of their studies.”

Another reviewer wrote: “This study is very interesting because it explores the mechanism by which the conserved transcription factor NRF/SKN-1 acts to regulate longevity in response to deficiencies in the germline. This study also highlights an intriguing and novel germline-to-soma signaling for lifespan. Because SKN-1 is highly conserved throughout evolution and plays a role in metabolism in mammals, this study has important ramifications for age-related diseases in higher organisms. This study will appeal to a broad audience, including the fields of lipid metabolism, proteostasis, aging, and signaling.”

However both reviewers raised some questions. Please address these comments in a revised version.

1) The authors used “GSC ablation” and “glp-1(ts)” interchangeably throughout the text beginning with the Introduction. While glp-1(ts) worms are defective in GSC production, they still produce a partial germline, whereas worms that have undergone laser ablation of the germline would not produce GSCs at all. The authors should either tone done their terminology or for a few key assays, test worms that have undergone actual surgical ablation of the germline?

2) Figure 4D: To make a statement regarding the role of rpn-6.1 in regulating glp-1(ts) proteostasis or longevity in general, the authors should consider more functional tests. For example, is rpn-6.1 required for glp-1(ts) longevity or for enhanced proteasome activity in glp-1(ts) worms.

3) Figure 6C/D suggests that excessive accumulation of yolk fat may drive SKN-1 activations in the intestine. Would worms treated with rme-2 RNAi, which presumably are high fat, exhibit high SKN-1 nuclear localization and beneficial phenotypes, such as stress resistance and longevity, associated with SKN-1 activation?

4) Figure 5–figure supplement 1: The DHS-3 gene encodes a fatty acid dehydrogenase/reductase that targets the mitochondria. The DHS-3 marker likely reveals levels of short chain fatty acid breakdown. Though the quantification data correlate with the ORO staining pattern in Figure 5B/C very well, is DHS-3::GFP an accurate marker for lipid accumulation or lipid breakdown? In other words, are authors using lipid breakdown as a predictor of lipid accumulation in this case? Furthermore, are SKN-1 and SBP-1 regulators of dhs-3 gene expression, where SKN-1 is a negative regulator and SBP-1 is positive regulator of dhs-3? If this is the case, one could expect a similar trend independently of lipid accumulation levels.

5) Are genes encoding vitellogenin proteins upregulated at the mRNA level in somatic tissues of GSC(−) worms? This might provide insight into whether high somatic VIT-2 levels are directly due to failure of vitellogenin import into oocytes or a transcriptional consequence of GCS loss.

6) While the overall point of the oil-red-o experiments is very convincing, there is a mismatch between the examples shown (Figure 5B,D) and the corresponding quantifications (Figure 5C,E). I recognize that this is really a problem of oil-red-o staining as it is not that suitable for quantification. One solution is to show a series of images for each condition in supplementary material so that the range of data can be seen. Alternatively (but not necessary), the authors can complement the studies by biochemical measurements of lipids.