A proteomic atlas of insulin signalling reveals tissue‐specific mechanisms of longevity assurance

Tain, Luke S; Sehlke, Robert; Jain, Chirag; Chokkalingam, Manopriya; Nagaraj, Nagarjuna; Essers, Paul; Rassner, M G; Grönke, Sebastian; Froelich, Jenny; Dieterich, Christoph; Mann, Matthias; Alic, Nazif; Beyer, Andreas; Partridge, Linda

doi:10.15252/msb.20177663

Cited by 41 publications

(62 citation statements)

References 127 publications

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“…The level of Gnmt was elevated in the fat body of long‐lived IIS mutant flies. This is in agreement with a recent proteomic study of an independent IIS mutant (Tain et al, ) which showed fat body‐specific increases in Gnmt, suggesting that increased Gnmt levels, and thus altered Met metabolism, may be a common feature of long‐lived IIS models. Recently, Gnmt expression was found to be elevated in long‐lived dietary restricted mice (Hahn et al, ), and increased Gnmt expression is a common feature of long‐lived Ames dwarf mice (Brown‐Borg, Borg, Meliska, & Bartke, ).…”

Section: Discussionsupporting

confidence: 92%

“…Studies examining the transcriptomic and proteomic changes that occur during aging, or in response to interventions that ameliorate its effects, have revealed several conserved prolongevity processes, including many metabolic changes (Afschar et al, ; Dobson et al, ; Hahn et al, ; Murphy et al, ; Narayan et al, ; Page et al, ; Stout et al, ; Tain et al, ; Teleman, Hietakangas, Sayadian, & Cohen, ). These include carbohydrate metabolism (Afschar et al, ), lipid and fatty acid metabolism (Dobson et al, ; Hahn et al, ; Murphy et al, ; Page et al, ), energy metabolism (Afschar et al, ), and protein and methionine (Met) metabolism (Narayan et al, ; Stout et al, ).…”

Section: Introductionmentioning

confidence: 99%

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Longevity in response to lowered insulin signaling requires glycine N‐methyltransferase‐dependent spermidine production

et al. 2019

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Reduced insulin/IGF signaling (IIS) extends lifespan in multiple organisms. Different processes in different tissues mediate this lifespan extension, with a set of interplays that remain unclear. We here show that, in Drosophila, reduced IIS activity modulates methionine metabolism, through tissue‐specific regulation of glycine N‐methyltransferase (Gnmt), and that this regulation is required for full IIS‐mediated longevity. Furthermore, fat body‐specific expression of Gnmt was sufficient to extend lifespan. Targeted metabolomics showed that reducing IIS activity led to a Gnmt‐dependent increase in spermidine levels. We also show that both spermidine treatment and reduced IIS activity are sufficient to extend the lifespan of Drosophila, but only in the presence of Gnmt. This extension of lifespan was associated with increased levels of autophagy. Finally, we found that increased expression of Gnmt occurs in the liver of liver‐specific IRS1 KO mice and is thus an evolutionarily conserved response to reduced IIS. The discovery of Gnmt and spermidine as tissue‐specific modulators of IIS‐mediated longevity may aid in developing future therapeutic treatments to ameliorate aging and prevent disease.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Longevity in response to lowered insulin signaling requires glycine N‐methyltransferase‐dependent spermidine production

et al. 2019

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“…Notably, some precedence suggests only a limited role for dfoxo as the mediator of reduced IIS in aging, as dfoxo only partially rescues longevity benefits of chico, revealing that IIS extends lifespan through some FOXO-independent pathways (Yamamoto & Tatar, 2011). On the other hand, our whole animal analysis of dFOXO targets may obscure its role in IIS signaling if IIS and FOXO regulate aging only through actions in a few specific tissues, as previously documented (Tain et al, 2017;Wolkow, Kimura, Lee, & Ruvkun, 2000). In this vein, we find that dilp2 controls thorax ERK signaling but not AKT, suggesting that dilp2 mutants may activate muscle-specific ERK/MAPK anti-aging programs, although their potential action through dFOXO remains to be determined.…”

Section: While Foxo (Dfoxo or Daf-16) Is Intimately Associated With Hmentioning

confidence: 57%

Drosophila insulin-like peptide dilp1 increases lifespan and glucagon-like Akh expression epistatic to dilp2

Post

Liao

Yamamoto

et al. 2018

Preprint

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Insulin/IGF signaling (IIS) regulates essential processes including development, metabolism, and aging. The Drosophila genome encodes eight insulin/IGF-like peptide (dilp) paralogs, including tandem-encoded dilp1 and dilp2. Many reports show that longevity is increased by manipulations that decrease DILP2 in adults. In contrast, dilp1 is expressed primarily in pupal stages, but also during adult reproductive diapause, although we find that dilp1 is also highly expressed in adult dilp2 mutants under non-diapause conditions. The inverse expression of dilp1 and dilp2 suggests these genes interact to regulate aging. Here, we study dilp1 and dilp2 single and double mutants to describe epistatic and synergistic interactions affecting longevity, metabolism and adipokinetic hormone (AKH), a functional homolog of glucagon. Mutants of dilp2 extend lifespan and increase Akh mRNA and protein in a dilp1dependent manner. Loss of dilp1 alone has no impact on these traits, whereas transgene expression of dilp1 increases lifespan in dilp1-dilp2 double mutants. On the other hand, dilp1and dilp2 redundantly interact to control circulating sugar, starvation resistance and compensatory dilp5 expression. These later interactions do not correlate with patterns for how dilp1 and dilp2 affect longevity and AKH. Thus, repression or loss of dilp2 slows aging because its depletion induces dilp1, which acts as a pro-longevity factor. Likewise, dilp2 regulates Akh through epistatic interaction with dilp1. Akh and glycogen affect aging in C. elegans and Drosophila, suggesting that dilp2 modulates lifespan via dilp1 and in part by regulating Akh.Whether DILP1 acts as an insulin receptor agonist or inhibitor remains to be resolved.

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“…The mass spectrometer was operated in a data-dependent mode with survey scans from 300 to 1,700 m/z (resolution of 60,000 at m/z = 200). Up to 15 of the top precursors were selected and fragmented using higher energy collisional dissociation (HCD) with a normalized collision energy value of 28 [59]. The MS2 spectra were recorded at a resolution of 17,500 (at m/z = 200).…”

Section: Cell Analysismentioning

confidence: 99%

“…AGC target for MS and MS2 scans were set to 3E6 and 1E5, respectively, within a maximum injection time of 100 and 25 ms for MS and MS2 scans, respectively. Dynamic exclusion was enabled to minimize repeated sequencing of the same precursor ions and set to 30 s [59].…”

Section: Cell Analysismentioning

confidence: 99%

Proteomics identifies signal peptide features determining the substrate specificity in human Sec62/Sec63-dependent ER protein import

Zimmermann

Lang

Schorr

et al. 2019

Preprint

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In mammalian cells one-third of all polypeptides are integrated into the membrane or translocated into the lumen of the endoplasmic reticulum (ER) via the Sec61-channel. While the Sec61-complex facilitates ER-import of most precursor polypeptides, the Sec61-associated Sec62/Sec63-complex supports ER-import in a substrate-specific manner. So far, mainly posttranslationally imported precursors and the two cotranslationally imported precursors of ERj3 and prion protein were found to depend on the Sec62/Sec63-complex in vitro. Therefore, we determined the rules for engagement of Sec62/Sec63 in ER-import in intact human cells using a recently established unbiased proteomics approach. In addition to confirming ERj3, we identified twenty-two novel Sec62/Sec63-substrates under these in vivo-like conditions. As a common feature, those previously unknown substrates share signal peptides with comparatively longer but less hydrophobic H-region and lower C-region polarity. Further analyses with four substrates, and ERj3 in particular, revealed the combination of a slowly-gating signal peptide and a downstream translocation-disruptive positively charged cluster of amino acid residues as decisive for the Sec62-/Sec63-requirement. In the case of ERj3, these features were found to be responsible for an additional BiP-requirement and to correlate with sensitivity towards the Sec61-channel inhibitor CAM741. Thus, the human Sec62/Sec63-complex may support Sec61-channel opening for precursor polypeptides with slowly-gating signal peptides by direct interaction with the cytosolic amino-terminal peptide of Sec61α or via recruitment of BiP and its interaction with the ER-lumenal loop 7 of Sec61α. These novel insights into the mechanism of human ER protein import contribute to our understanding of the etiology of SEC63-linked Polycystic Liver Disease.DatabasesThe mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository (http://www.ebi.ac.uk/pride/archive/projects/Identifiers) with the dataset identifiers: PXD008178, PXD011993, and PXD012078. Supplementary information was deposited at Mendeley Data under the DOI:10.17632/6s5hn73jcv.1 (http://dx.doi.or/10.17632/6s5hn73jcv.1).

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A proteomic atlas of insulin signalling reveals tissue‐specific mechanisms of longevity assurance

Cited by 41 publications

References 127 publications

Longevity in response to lowered insulin signaling requires glycine N‐methyltransferase‐dependent spermidine production

Longevity in response to lowered insulin signaling requires glycine N‐methyltransferase‐dependent spermidine production

Drosophila insulin-like peptide dilp1 increases lifespan and glucagon-like Akh expression epistatic to dilp2

Proteomics identifies signal peptide features determining the substrate specificity in human Sec62/Sec63-dependent ER protein import

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