Aging and Longevity: Short and sweet
A truncated version of the only insulin receptor in C. elegans has been discovered.
- Department of Molecular Biology, Princeton University, United States
- LSI Genomics, Princeton University, United States
It would be hard to overstate the importance of a receptor called DAF-2 to our understanding of aging and longevity. Almost 30 years ago it was discovered that loss of the daf-2 gene doubles lifespan in the worm C. elegans (Kenyon et al., 1993), and a few years later it was reported that DAF-2 is the only insulin/IGF-1-like receptor in C. elegans (Kimura et al., 1997). These findings led to an explosion of research into aging and longevity, revealing an intricate insulin signaling pathway that coordinates the sensing of nutrient levels with the regulation of age-related decline. In particular, it was found that reduced insulin signaling extends lifespan and increases stress resistance in flies and mice (Clancy et al., 2001; Holzenberger et al., 2003). Moreover, mutations in some of the genes associated with this pathway were found in centenarians (Suh et al., 2008). And in worms it became clear that, in addition to longevity and age-related declines, DAF-2 is involved in the regulation of a wide range of biological processes, including development, reproduction, memory, and stress responses.
DAF-2 was originally discovered for its role in controlling the dauer stage – an alternative stage of development in which a larva goes into a type of stasis to help it survive harsh conditions (Riddle et al., 1981). A lack of DAF-2 causes C. elegans to enter dauer, as does a lack of a number of other kinases (Paradis and Ruvkun, 1998). An ongoing mystery is why C. elegans has just a single gene for an insulin receptor despite having 40 different insulin-like peptides (Pierce et al., 2001). Some of these peptides are agonists (that is, they activate the receptor) and others are antagonists (they inhibit the receptor).
Given three decades of extensive research into the insulin signaling pathway in C. elegans, it would be shocking to find new functions for DAF-2 at this point. However, in a new paper in eLife, Matthew Gill of the Scripps Research Institute and colleagues – including Bryan Martinez and Pedro Reis Rodrigues as joint first authors – report evidence for such a shock: the gene for DAF-2 can also express another, truncated isoform of this protein as a result of alternative splicing (Martinez et al., 2020). The truncated version, which is called DAF-2B, can still form dimers but, unlike the full-length version, it is not expected to be able to span the membrane: this suggests that the truncated form could be secreted.
Truncated insulin receptors that have extracellular ligand-binding domains, but lack intracellular signaling domains, have been reported in both Drosophila and mammals, and are known to sequester insulin peptides. However, in these cases the full-length receptors and the truncated receptors are expressed from separate genes. Martinez et al. found that although DAF-2B was expressed in neuronal cells, it accumulated in cells called coelomocytes (macrophage-like cells that attack invading organisms such as bacteria and viruses). These results suggest that DAF-2B can indeed be secreted, rather than being retained in the neurons in which it is expressed and spliced.
But what does this shortened form of DAF-2 do? The best-characterized functions of the insulin signaling pathway are dauer formation and lifespan regulation, so Martinez et al. used these phenotypes to study DAF-2B. They found that overexpressing DAF-2B increased dauer formation, slowed dauer exit, and increased lifespan, whereas a lack of DAF-2B had the opposite effect. Basically, the data suggest that the function of DAF-2B is essentially the opposite of the function of DAF-2.
Martinez et al. also explored the interactions between DAF-2B and insulin-like peptides that were either agonists or antagonists. Overexpression of two peptides that are agonists (DAF-28 and INS-6) reduced the dauer-promoting effects of DAF-2B. Conversely, the overexpression of a peptide that is an antagonist (INS-18) would be expected to promote dauer, but this effect was blunted when DAF-2B was also overexpressed. Additionally, the researchers found that a point mutation in the proposed insulin-binding domain resulted in a form of DAF-2B that exhibited reduced dauer formation. Together, these results suggest that DAF-2B binds and may sequester insulin-like peptides, and/or form dimers with DAF-2.
Of course, mysteries remain. Given that worms have dozens of insulin-like peptides (Pierce et al., 2001), which of these bind to DAF-2B, and under what circumstances? And if DAF-2B is secreted, why does it matter where it is expressed, unless there are highly localized interactions? Finally, the mechanism by which DAF-2B acts and its dimerization state is not entirely understood.
The discovery of the truncated version of DAF-2, and the fact that it essentially works in opposition to the full-length version, raises new questions and will change how we think about DAF-2's role in insulin signaling regulation of aging and longevity.
References
Article and author information
Author details
Publication history
- Version of Record published: February 25, 2020 (version 1)
Copyright
© 2020, Murphy
This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 3,038
- views
-
- 168
- downloads
-
- 1
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Aging and Longevity: Short and sweet
eLife 9:e55220.
https://doi.org/10.7554/eLife.55220
Further reading
-
- Developmental Biology
- Structural Biology and Molecular Biophysics
A crucial event in sexual reproduction is when haploid sperm and egg fuse to form a new diploid organism at fertilization. In mammals, direct interaction between egg JUNO and sperm IZUMO1 mediates gamete membrane adhesion, yet their role in fusion remains enigmatic. We used AlphaFold to predict the structure of other extracellular proteins essential for fertilization to determine if they could form a complex that may mediate fusion. We first identified TMEM81, whose gene is expressed by mouse and human spermatids, as a protein having structural homologies with both IZUMO1 and another sperm molecule essential for gamete fusion, SPACA6. Using a set of proteins known to be important for fertilization and TMEM81, we then systematically searched for predicted binary interactions using an unguided approach and identified a pentameric complex involving sperm IZUMO1, SPACA6, TMEM81 and egg JUNO, CD9. This complex is structurally consistent with both the expected topology on opposing gamete membranes and the location of predicted N-glycans not modeled by AlphaFold-Multimer, suggesting that its components could organize into a synapse-like assembly at the point of fusion. Finally, the structural modeling approach described here could be more generally useful to gain insights into transient protein complexes difficult to detect experimentally.
-
- Developmental Biology
Inhibitory G alpha (GNAI or Gαi) proteins are critical for the polarized morphogenesis of sensory hair cells and for hearing. The extent and nature of their actual contributions remains unclear, however, as previous studies did not investigate all GNAI proteins and included non-physiological approaches. Pertussis toxin can downregulate functionally redundant GNAI1, GNAI2, GNAI3, and GNAO proteins, but may also induce unrelated defects. Here, we directly and systematically determine the role(s) of each individual GNAI protein in mouse auditory hair cells. GNAI2 and GNAI3 are similarly polarized at the hair cell apex with their binding partner G protein signaling modulator 2 (GPSM2), whereas GNAI1 and GNAO are not detected. In Gnai3 mutants, GNAI2 progressively fails to fully occupy the sub-cellular compartments where GNAI3 is missing. In contrast, GNAI3 can fully compensate for the loss of GNAI2 and is essential for hair bundle morphogenesis and auditory function. Simultaneous inactivation of Gnai2 and Gnai3 recapitulates for the first time two distinct types of defects only observed so far with pertussis toxin: (1) a delay or failure of the basal body to migrate off-center in prospective hair cells, and (2) a reversal in the orientation of some hair cell types. We conclude that GNAI proteins are critical for hair cells to break planar symmetry and to orient properly before GNAI2/3 regulate hair bundle morphogenesis with GPSM2.
