Summary
Metformin, an FDA‐approved antidiabetic drug, has been shown to elongate lifespan in animal models. Nevertheless, the effects of metformin on human cells remain unclear. Here, we show that ...low‐dose metformin treatment extends the lifespan of human diploid fibroblasts and mesenchymal stem cells. We report that a low dose of metformin upregulates the endoplasmic reticulum‐localized glutathione peroxidase 7 (GPx7). GP×7 expression levels are decreased in senescent human cells, and GPx7 depletion results in premature cellular senescence. We also indicate that metformin increases the nuclear accumulation of nuclear factor erythroid 2‐related factor 2 (Nrf2), which binds to the antioxidant response elements in the GPX7 gene promoter to induce its expression. Moreover, the metformin‐Nrf2‐GPx7 pathway delays aging in worms. Our study provides mechanistic insights into the beneficial effects of metformin on human cellular aging and highlights the importance of the Nrf2‐GPx7 pathway in pro‐longevity signaling.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Piwi-interacting RNAs (piRNAs) are genomically encoded small RNAs that engage Piwi Argonaute proteins to direct mRNA surveillance and transposon silencing. Despite advances in understanding piRNA ...pathways and functions, how the production of piRNA is regulated remains elusive. Here, using a genetic screen, we identify casein kinase II (CK2) as a factor required for piRNA pathway function. We show that CK2 is required for the localization of PRG-1 and for the proper localization of several factors that comprise the 'upstream sequence transcription complex' (USTC), which is required for piRNA transcription. Loss of CK2 impairs piRNA levels suggesting that CK2 promotes USTC function. We identify the USTC component twenty-one-U fouled-up 4 (TOFU-4) as a direct substrate for CK2. Our findings suggest that phosphorylation of TOFU-4 by CK2 promotes the assembly of USTC and piRNA transcription. Notably, during the aging process, CK2 activity declines, resulting in the disassembly of USTC, decreased piRNA production, and defects in piRNA-mediated gene silencing, including transposons silencing. These findings highlight the significance of posttranslational modification in regulating piRNA biogenesis and its implications for the aging process. Overall, our study provides compelling evidence for the involvement of a posttranslational modification mechanism in the regulation of piRNA biogenesis.
Eukaryotic cells use guided search to coordinately control dispersed genetic elements. Argonaute proteins and their small RNA cofactors engage nascent RNAs and chromatin-associated proteins to direct ...transcriptional silencing. The small ubiquitin-like modifier (SUMO) has been shown to promote the formation and maintenance of silent chromatin (called heterochromatin) in yeast, plants, and animals. Here, we show that Argonaute-directed transcriptional silencing in
requires SUMOylation of the type 1 histone deacetylase HDA-1. Our findings suggest how SUMOylation promotes the association of HDAC1 with chromatin remodeling factors and with a nuclear Argonaute to initiate de novo heterochromatin silencing.
Abstract
Background
The accelerated aging trend brought great chronic diseases burdens. Disabled Adjusted Life Years (DALYs) is a novel way to measure the chronic diseases burden. This study aimed to ...explore the cohort, socioeconomic status (SES), and gender disparities of the DALYs trajectories.
Methods
A total of 15,062 participants (55,740 observations) comes from China Health and Retirement Longitudinal Study (CHARLS) from 2011 to 2018. Mixed growth curve model was adopted to predict the DALYS trajectories in 45–90 years old people influenced by different birth cohorts and SES.
Results
We find significant cohort, SES (resident place, education level and income) disparities differences in the chronic diseases DALYs. For individuals of earlier cohort, DALYs are developed in a late age but grow fast with age but reversed for most recent cohorts. Living in urban, having higher SES level will decrease the growth rate with age, but converges for most recent cohorts. Meanwhile, DALYs disparities of resident place and education level show gender differentials that those for female are narrowed across cohort but for male are not.
Conclusions
The cohort effects on chronic diseases DALYs are accumulated with China’s unique social, and political settings. There are large inequalities in early experiences, SES and DALYs. Efforts of reducing these inequalities must focus on the lower SES individuals and those living in rural areas, which greatly benefit individuals from recent cohorts.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Sec61β, a subunit of the Sec61 translocon complex, is not essential in yeast and commonly used as a marker of endoplasmic reticulum (ER). In higher eukaryotes, such as Drosophila, deletion of Sec61β ...causes lethality, but its physiological role is unclear. Here, we show that Sec61β interacts directly with microtubules. Overexpression of Sec61β containing small epitope tags, but not a RFP tag, induces dramatic bundling of the ER and microtubule. A basic region in the cytosolic domain of Sec61β is critical for microtubule association. Depletion of Sec61β induces ER stress in both mammalian cells and Caenorhabditis elegans, and subsequent restoration of ER homeostasis correlates with the microtubule binding ability of Sec61β. Loss of Sec61β causes increased mobility of translocon complexes and reduced level of membrane-bound ribosomes. These results suggest that Sec61β may stabilize protein translocation by linking translocon complex to microtubule and provide insight into the physiological function of ER-microtubule interaction.
Numerous cellular functions occur in spatially and temporally confined regions. Recent studies have shown that membrane-less organelles and compartments in the cell are assembled via liquid–liquid ...phase separation (LLPS).
In vitro
LLPS assays using recombinant expressed and purified proteins are necessary for us to further understand how the assembly of phase-separated compartments is regulated in cells. However, uniform standards and protocols are lacking for these
in vitro
studies. Here, we describe a step-by-step protocol commonly used to investigate
in vitro
LLPS using purified proteins. This protocol includes expression and purification of the studied proteins, induction of LLPS of the purified proteins, and studies of the biophysical properties of the liquid droplets formed by LLPS. These protocols can be easily followed by researchers to investigate the LLPS behaviors of proteins of interest.
The assembly of phase-separated structures is thought to play an important role in development and disease, but little is known about the regulation and function of phase separation under ...physiological conditions. We showed that during C. elegans embryogenesis, PGL granules assemble via liquid-liquid phase separation (LLPS), and their size and biophysical properties determine their susceptibility to autophagic degradation. The receptor SEPA-1 promotes LLPS of PGL-1/-3, while the scaffold protein EPG-2 controls the size of PGL-1/-3 compartments and converts them into less dynamic gel-like structures. Under heat-stress conditions, mTORC1-mediated phosphorylation of PGL-1/-3 is elevated and PGL-1/-3 undergo accelerated phase separation, forming PGL granules that are resistant to autophagic degradation. Significantly, accumulation of PGL granules is an adaptive response to maintain embryonic viability during heat stress. We revealed that mTORC1-mediated LLPS of PGL-1/-3 acts as a switch-like stress sensor, coupling phase separation to autophagic degradation and adaptation to stress during development.
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•The receptor protein SEPA-1 promotes liquid-liquid phase separation of PGL granules•The scaffold protein EPG2 determines the size and gel-like state of PGL granules•mTORC1-mediated phosphorylation promotes LLPS of PGL granules•PGL granules confer heat-stress resistance on embryos
mTORC1 signaling modulates phase separation of PGL granules to orchestrate their autophagic degradation and heat stress adaptation during C. elegans embryogenesis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Mutations in the human autophagy gene EPG5 cause the multisystem disorder Vici syndrome. Here we demonstrated that EPG5 is a Rab7 effector that determines the fusion specificity of autophagosomes ...with late endosomes/lysosomes. EPG5 is recruited to late endosomes/lysosomes by direct interaction with Rab7 and the late endosomal/lysosomal R-SNARE VAMP7/8. EPG5 also binds to LC3/LGG-1 (mammalian and C. elegans Atg8 homolog, respectively) and to assembled STX17-SNAP29 Qabc SNARE complexes on autophagosomes. EPG5 stabilizes and facilitates the assembly of STX17-SNAP29-VAMP7/8 trans-SNARE complexes, and promotes STX17-SNAP29-VAMP7-mediated fusion of reconstituted proteoliposomes. Loss of EPG5 activity causes abnormal fusion of autophagosomes with various endocytic vesicles, in part due to elevated assembly of STX17-SNAP25-VAMP8 complexes. SNAP25 knockdown partially suppresses the autophagy defect caused by EPG5 depletion. Our study reveals that EPG5 is a Rab7 effector involved in autophagosome maturation, providing insight into the molecular mechanism underlying Vici syndrome.
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•EPG5 is a Rab7 effector that mediates fusion of autophagosomes with late endosomes•EPG5 facilitates the assembly of trans-SNARE complexes for autophagosome fusion•EPG5 is recruited to late endosomes/lysosomes by binding to Rab7 and VAMP7/8•EPG5 interacts with LC3/LGG-1 and assembled autophagosomal SNARE Qabc complexes
Wang et al. demonstrate that the Vici syndrome protein EPG5 acts as a tethering factor that determines the fusion specificity of autophagosomes with late endosomes/lysosomes. EPG5 stabilizes and facilitates assembly of the trans-SNARE complex that mediates autophagosome maturation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The mechanisms that specify and maintain the charac- teristics of germ cells during animal development are poorly understood. In this study, we demonstrated that loss of function of the zinc-finger ...gene Isy-2 results in various somatic cells adopting germ cells characteris- tics, including expression of germline-specific P gran- ules, enhanced RNAi activity and transgene silencing. The soma to germ transformation in Isy-2 mutants requires the activities of multiple chromatin remodeling complexes, including the MES-4 complex and the ISW-1 complex. The distinct germline-specific features in somatic cells and the gene expression profile indicate that LSY-2 acts in the Mec complex in this process. Our study demonstrated that Isy-2 functions in the mainte- nance of the soma-germ distinction.
A graphene nanosheet/ultra-high molecular weight polyethylene composite with a segregated structure has been fabricated using water/ethanol solvent-assisted dispersion and hot compression at 200
°C. ...A percolation threshold as low as 0.070
vol.% has been achieved because of the formation of a two-dimensional conductive network.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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