Dataset Information

Quantitative proteome for C.elegans by 3plex mTRAQ

ABSTRACT: Vesicle-mediated transport is a fundamental part of the secretory and endocytic pathways. In addition to their role in membrane protein trafficking, Arf-like protein subfamily of small GTPases also plays an important role in development, maintenance of Golgi structure and function. Proper protein trafficking is critical for cellular integrity and studies demonstrate that aberrant protein sorting leads to various diseases in many organisms including humans. However, to date, there is no report showing the role of Golgi apparatus and Golgi proteins in organismal longevity. Organisms dynamically reprogram their transcriptome and proteome as a response to internal and external changes, which alter physiological processes including aging. Compared to many transcriptomic studies that identified aging-regulatory genes, proteomic studies that identified aging-regulatory proteins are relatively scarce. By using a quantitative proteomic approach, we identified MON-2, an Arf-Gef protein implicated in Golgi-to-endosome trafficking, as a longevity-promoting protein. We found that MON-2 is essential for the long lifespan of various longevity mutants. Our results demonstrate that Golgi-to-endosome trafficking is an integral part of lifespan regulation.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Caenorhabditis Elegans

SUBMITTER: Shinyeong Ju

LAB HEAD: Cheolju Lee

PROVIDER: PXD026411 | Pride | 2022-02-17

REPOSITORIES: Pride

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Publications

MON-2, a Golgi protein, mediates autophagy-dependent longevity in <i>Caenorhabditis elegans</i>.

Jung Yoonji Y Artan Murat M Kim Nari N Yeom Jeonghun J Hwang Ara B AB Jeong Dae-Eun DE Altintas Özlem Ö Seo Keunhee K Seo Mihwa M Lee Dongyeop D Hwang Wooseon W Lee Yujin Y Sohn Jooyeon J Kim Eun Ji E EJE Ju Sungeun S Han Seong Kyu SK Nam Hyun-Jun HJ Adams Linnea L Ryu Youngjae Y Moon Dong Jin DJ Kang Chanhee C Yoo Joo-Yeon JY Park Sang Ki SK Ha Chang Man CM Hansen Malene M Kim Sanguk S Lee Cheolju C Park Seung-Yeol SY Lee Seung-Jae V SV

Science advances 20211203 49

The Golgi apparatus plays a central role in trafficking cargoes such as proteins and lipids. Defects in the Golgi apparatus lead to various diseases, but its role in organismal longevity is largely unknown. Using a quantitative proteomic approach, we found that a Golgi protein, MON-2, was up-regulated in long-lived <i>Caenorhabditis elegans</i> mutants with mitochondrial respiration defects and was required for their longevity. Similarly, we showed that DOP1/PAD-1, which acts with MON-2 to traff ...[more]

PMID: 34860542

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Project description:One of the most important issues in the study of aging is to discover compounds with longevity-promoting activity and to unravel their underlying mechanisms. Queen honey bees are continuously fed royal jelly (RJ), and they live more than 10 times longer than hive workers, derived from the same diploid genome, which are fed it only for a short period of time during their larval stages. Therefore, RJ is likely to contain longevity-promoting agents for queens. RJ has been reported to possess diverse pharmacological properties. Furthermore, protease-treated RJ (pRJ) has additional beneficial activities. How RJ and pRJ exert these effects and which components in them play a critical role is largely unknown. The evolutionally conserved mechanisms that control lifespan have been indicated. The nematode Caenorhabditis elegans has been widely used for study of aging and longevity, due to its relatively short lifespan and well-established genetic pathways. The purpose of the present study was to elucidate whether RJ and its related substances contain the life span-extending activity in C. elegans and to obtain some insight into the active agents and their mechanisms. We found that both RJ and pRJ extended the lifespan of C. elegans. The life span-extending activity of pRJ was enriched by ODS column chromatography (pRJ-Fraction 5). pRJ-Fr. 5 extended the life span partly by acting through the FOXO transcription factor DAF-16, the activation of which is known to promote longevity in C. elegans by reducing insulin/IGF-1 signaling (IIS). pRJ-Fr. 5 induced changes in the expression of 3 genes encoding insulin-like peptides. Moreover, pRJ-Fr. 5 and reduced IIS shared some common features in terms of their effect on gene expression, such as up-regulation of dod-3 and down-regulation of dod-19, dao-4 and fkb-4. The dod-19 is a previously identified life span determinant in C. elegans, and the fkb-4 encodes a homologue of the mammalian FK506-binding protein. 10-Hydroxy-2-decenoic acid (10-HDA), which was present in high concentration in pRJ-Fr. 5, increased the lifespan independently of DAF-16 activity.These results demonstrate that RJ and its related substances extended the life span in C. elegans, suggesting that RJ may contain longevity-promoting factors common to diverse species across phyla. pRJ-Fr. 5 had higher life span-extending activity than either RJ or pRJ and extended the life span in part through the IIS-DAF-16 pathway. We provide the first evidence that 10-HDA, a defined natural product in RJ, extended organismal lifespan. It is noteworthy that 10-HDA performed its lifespan-extending function through a mechanism totally different from the IIS-DAF-16 pathway. Further search and characterization of the lifespan-extending agents in RJ and pRJ may broaden our understanding of the gene network of longevity regulation in diverse species and provide the possibility for nutraceutical interventions in the aging process. C. elegans N2 hermaphrodites were untreated or treated with pRJ-Fr. 5 (25mg/ml) for 24 h starting at the larval 4 (L4) stage.

Project description:Low energy states delay aging in multiple species, yet mechanisms coordinating energetics and longevity across tissues remain poorly defined. The conserved energy sensor AMP-activated protein kinase (AMPK) and its corresponding phosphatase calcineurin modulate longevity via the ‘CREB regulated transcriptional coactivator (CRTC)-1 in C. elegans. We show that CRTC-1 specifically uncouples AMPK/calcineurin mediated effects on lifespan from pleiotropic side effects by reprogramming mitochondrial and metabolic function. Strikingly, this pro-longevity metabolic state is regulated cell-nonautonomously by CRTC-1 in the nervous system. CRTC-1/CREB act antagonistically with the functional PPARα ortholog, NHR-49 to promote distinct peripheral metabolic programs. Neuronal CRTC-1 drives mitochondrial fragmentation in distal tissues and suppresses the effect of AMPK on systemic mitochondrial metabolism and longevity via a cell-nonautonomous catecholamine signal. These results demonstrate that transcriptional control of neuronal signals can override enzymatic regulation of metabolism in peripheral tissues. Central perception of energetic state therefore represents a target to promote healthy aging. Experiment was performed with three biological replicates. Gravid adults grown at 20¡C on 100 mm NG plates seeded with OP50-1 E. coli were collected and treated with hypochlorite to release eggs. Eggs were incubated overnight in M9 media to obtain L1 synchronized populations. One thousand L1 larvae were grown on a 100 mm NG plate seeded with OP50-1 E. coli. Worms were harvested for RNA extraction when L4 larval stage was reached. Animals were collected and washed extensively with M9 media to remove bacteria. Worms were then snap frozen in liquid nitrogen. RNA was extracted by five freeze/thaw cycles in Qiazol then purified by RNeasy mini kit (Qiagen). RNA quality was checked using an Agilent Technologies 2100 Bioanalyzer. All samples had an RNA integrity number of 10. cDNA libraries were prepared from 4 ugs of total RNA using the TruSeq RNA Sample Preparation v2 kit (Illumina). 50-cycle paired-end sequencing was performed on an Illumina HiSeq 2000 by the Harvard Biopolymer Core. Read quality was evaluated with FASTQC. Adapter sequences and poor quality bases (<20) were trimmed and filtered with CUTADAPT, resulting in a median of 44 million reads per replicate. These were aligned to the C. elegans genome (ce6, WS238) using TopHat version 2.0.8 (Kim et al., 2013), with a median 35 million reads mapped in proper pairs. The number of reads mapping to each gene was counted with htseq-count. Genes with less than 1 Count Per Million Reads (CPM) were discarded from further analysis. Counts were normalized for sequencing depth and RNA composition across all samples with edgeR (Robinson et al., 2010). Genes were tested for differential expression between each mutant strain and wild-type using edgeR’s glm method. For each comparison, genes with less than 5 CPM were filtered and those with at least 50% change and False Discovery Rate (FDR) of 1% or less were considered differentially expressed.

Dataset Information

Quantitative proteome for C.elegans by 3plex mTRAQ

Publications

MON-2, a Golgi protein, mediates autophagy-dependent longevity in <i>Caenorhabditis elegans</i>.

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