Cytoplasmic LSM-1 protein regulates stress responses through the insulin/IGF-1 signaling pathway in Caenorhabditis elegans

Abstract

Genes coding for members of the Sm-like (LSm) protein family are conserved through evolution from prokaryotes to humans. These proteins have been described as forming homo-or heterocomplexes implicated in a broad range of RNA-related functions. To date, the nuclear LSm2-8 and the cytoplasmic LSm1-7 heteroheptamers are the best characterized complexes in eukaryotes. Through a comprehensive functional study of the LSm family members, we found that lsm-1 and lsm-3 are not essential for C. elegans viability, but their perturbation, by RNAi or mutations, produces defects in development, reproduction, and motility. We further investigated the function of lsm-1, which encodes the distinctive protein of the cytoplasmic complex. RNA-seq analysis of lsm-1 mutants suggests that they have impaired Insulin/IGF-1 signaling (IIS), which is conserved in metazoans and involved in the response to various types of stress through the action of the FOXO transcription factor DAF-16. Further analysis using a DAF-16::GFP reporter indicated that heat stress-induced translocation of DAF-16 to the nuclei is dependent on lsm-1. Consistent with this, we observed that lsm-1 mutants display heightened sensitivity to thermal stress and starvation, while overexpression of lsm-1 has the opposite effect. We also observed that under stress, cytoplasmic LSm proteins aggregate into granules in an LSM-1-dependent manner. Moreover, we found that lsm-1 and lsm-3 are required for other processes regulated by the IIS pathway, such as aging and pathogen resistance.

Neuronal function of the mRNA decapping complex determines survival ofCaenorhabditis elegansat high temperature through temporal regulation of heterochronic gene expression

“…Moreover, we noted that this lin-14::gfp transgene further enhanced the slow development of dcap-1 mutants, at 25°C (figure 7 a ). At this temperature, dcap-1 as well as dcap-2 and lsm-1 mutants tend to be asynchronous, even after tightly synchronous egg-laying, whereas adults exhibit egg-laying defects, reduced fertility and uncoordinated movement [36,39]. Intrigued by the dysregulation of lin-14 in decapping mutants in response to high temperature, we investigated whether the levels of lin-14 mRNA are also affected in dcap-1 mutant worms during normal development at 25°C.…”

“…Interestingly, when we measured the mRNA levels of lin-14 in young adults from all strains, we observed a significant increase in decapping mutants, compared with wild-type animals (figure 7 c ). Therefore, it is plausible to speculate that the upregulation of lin-14 mRNA levels during adulthood could contribute to or even account for the short lifespan of decapping mutants [36,39], given that lin-4 and lin-14 genes function to regulate ageing, with reduced lin-14 activity extending the lifespan of worms [65].

Figure 7.Decapping activity influences heterochronic gene expression and growth rate during normal development.

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“…In C. elegans , mutants in components of the 5′–3′ mRNA decay pathway display pleiotropic phenotypes, revealing their importance in diverse physiological processes, such as development, reproduction, stress response and ageing [36,37,39,68–70]. However, there is little information so far about their influence on specific mRNAs, which lead to the observed phenotypes when dysregulated.…”

Splicing-related Retinitis Pigmentosa mutations mimicked in C. elegans allow the identification of disease modifiers and drug screens

“…The effect of the drug in wild-type and prp-8(cer14) mutant animals was scored at adult stages ( Figure 4A). To better characterize the efficacy of our collection of drugs, after three days of exposure we quantified the locomotor activity of the worms for 15 minutes using the wmicrotracker device (25).…”

LSM2-8 and XRN-2 contribute to the silencing of H3K27me3-marked genes through targeted RNA decay

“…S1A). The two LSM complexes, LSM1-7 (cytoplasmic) and , were shown to function in RNA metabolism and splicing, but not in transcription per se (Beggs, 2005;Cornes et al, 2015;Golisz et al, 2013;Kufel et al, 2004;Perea-Resa et al, 2012;Tharun, 2009). The cytoplasmic LSM1-7 complex partners with decapping enzymes, which render RNA sensitive to the 5' to 3' XRN-1 exonuclease activity, while the LSM2-8 complex has been proposed to work with XRN-2 to promote nuclear RNA decay (Beggs, 2005;Tharun, 2009).…”